Modulation of inflammatory and metastatic processes

ABSTRACT

Methods of using compounds having Structure I or the salts or tautomers of the compounds in the treatment of disorders relating to cell adhesion and metastatic processes are presented herein.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 60/546,395 filed Feb. 20, 2004, U.S. Provisional Application No. 60/547,103 filed Feb. 23, 2004, and U.S. Provisional Application No. 60/554,771 filed Mar. 19, 2004, the entire disclosures of which are each incorporated herein by reference and for all purposes as if fully set forth herein.

FIELD OF THE INVENTION

The present invention provides methods for using compounds to modulate inflammatory responses and processes related to tumor metastasis. The invention further provides methods for monitoring the effects of the compounds of the invention by measuring the levels of ICAM, VCAM, or E-selectin molecules in a subject treated with the compounds.

BACKGROUND OF THE INVENTION

Amino quinolinone benzimidazolyl compounds such as 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one and their tautomers and salts are potent inhibitors of various class kinases such as VEGFR2 (KDR, Flk-1), FGFR1 and PDGFRβ with IC₅₀s ranging from 10-27 nM. See U.S. Pat. No. 6,605,617, U.S. patent application Ser. No. 10/644,055, and U.S. patent application Ser. No. 10/706,328, each of which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein, for a list of various tyrosine and serine/threonine kinases for which 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one has shown activity and for assay procedures. Such kinases are important for the initiation and maintenance of new blood vessel growth as well as tumor proliferation. Consequently these inhibitors have direct applications in the treatment of various disorders such as solid and hematological cancers. The identification of plasma biomarkers in subjects treated with these kinase inhibitors would therefore provide a convenient method for monitoring the subject's physiological response to the treatment.

Cell adhesion molecules play important roles in tumor cell invasion, metastasis, and interaction with immune cells. VCAM (vascular cell adhesion molecule) is a transmembrane glycoprotein and expressed in endothelial cells and various cancer types such as bladder, breast, gastrointestinal, ovarian, renal, and Hodgkin's and non-Hodgkin's lymphoma. VCAM is induced by VEGF and is predominantly expressed in activated endothelial cells. ICAM (inducible cell adhesion molecule) is also expressed in endothelial cells and various cells including fibroblasts, hematopoietic cells, and tumor cells. The soluble form of ICAM present in the plasma is generated by proteolytic cleavage of membrane-associated molecules. E-Selectin (endothelial leukocyte adhesion molecule) is a transmembrane glycoprotein expressed in endothelial cells and mediates adhesion of neutrophils, monocytes, and T cells to endothelial cells. E-selectin also mediates tumor progression and metastasis.

A high concentration of soluble ICAM, VCAM, and E-selectin is considered a marker of endothelial cell activation during tumor development, metastasis, and inflammatory responses. These cell adhesion molecules localized on endothelial cells can mediate adhesion of metastatic tumor cells and allow extravasation into the vessels. It is of interest that these molecules are inducible, being poorly expressed on normal endothelial cells but capable of being expressed highly after exposure to cytokines such as IL-1 or TNF-a. In addition, some of these molecules are preferentially expressed in different vascular beds, with VCAM being abundant in the lung and E-selectin in the liver.

Matrix metalloproteases (MMPs) are a class of proteases that degrade most components of the extracellular matrix (ECM). Under normal physiological conditions they play an important role in development, tissue remodeling and morphogenesis. However, elevated levels of certain metalloproteases have been implicated in pathological diseases such as cancer and inflammation. Degradation of the extracellular matrix in the basement membrane is essential for tissue invasion by tumor cells and metastasis at various sites, and this degradation is dependent on the activity of MMPs. The family of MMPs includes more than 20 members. Two of these proteases are MMP-2 (gelatinase A, 72 KD) and MMP-9 (gelatinase B, 92 KD). MMP-2 and MMP-9 are important regulators of cancer progression and metastasis and their levels are frequently elevated in various cancer patients.

A report by Bergers et al. (Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis; Berger, G. et al., Nature Cell Biology, 2:737-744; 2000) discloses that MMP-9/gelatinase B is a functional component of an angiogenic switch during multistage pancreatic carcinogenesis by increasing the release of VEGF.

Various quinolinone benzimidazole compounds useful in inhibiting angiogenesis and vascular endothelial growth factor receptor tyrosine kinases and in inhibiting other tyrosine and serine/threonine kinases including 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one or a tautomer thereof and the synthesis thereof are disclosed in the following documents which are each hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein: U.S. Pat. No. 6,605,617; U.S. Pat. No. 6,756,383; U.S. patent application Ser. No. 10/116,117 filed (published on Feb. 6, 2003, as U.S. 2003/0028018 A1); U.S. patent application Ser. No. 10/644,055 (published on May 13, 2004, U.S. Patent Application No. 2004/0092535); U.S. patent application Ser. No. 10/983,174; U.S. patent application Ser. No. 10/706,328 (published on Nov. 4, 2004, as 2004/0220196); U.S. patent application Ser. No. 10/982,757; and U.S. patent application Ser. No. 10/982,543.

An important need exists for methods for modulating levels of cellular adhesion molecules and matrix metalloproteases. Such methods would therefore constitute important and needed therapies in the treatment of inflammatory and metastatic diseases mediated by cellular adhesion molecules and matrix metalloproteases.

SUMMARY OF THE INVENTION

The present invention relates to methods of treating a human or animal subject with, and uses in a human or animal subject of, a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The invention also relates to the use of the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof in the preparation of a medicament for use in the methods described herein.

In one aspect, the invention provides a method of modulating an inflammatory response or reducing cellular adhesion in a subject. Such methods include administering to the subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The inflammatory response is modulated in the subject and/or cellular adhesion is reduced in the subject after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.

In one aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to modulate an inflammatory response.

In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to reduce cellular adhesion.

In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to decrease ICAM, VCAM, or E-selectin levels.

In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof used to reduce the levels of circulating cell adhesion molecules.

In another aspect, the compound, tautomer, salt of the compound, salt of the tautomer, or the mixture thereof are used to decrease circulating ICAM, VCAM, or E-selectin levels.

In another aspect, the invention provides a method of monitoring the progression of a disease or treatment in a human or animal subject. The method includes measuring the amount of at least one cell adhesion molecule in the subject after administration of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-Selectin). Some such methods further include withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample. Other embodiments include administering the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject.

In another aspect, the invention provides a method of identifying a subject in need of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The method includes measuring the amount of at least one cell adhesion molecule in the subject before, during, or after administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule. In some embodiments, the method further includes administering the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject after measuring the amount of the cell adhesion molecule in the subject.

Structure I has the following formula:

-   -   wherein,     -   R¹, R², R³, and R⁴ may be the same or different and are         independently selected from the group consisting of H, Cl, Br,         F, I, —CN, —NO₂, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷ groups, substituted         and unsubstituted amidinyl groups, substituted and unsubstituted         guanidinyl groups, substituted and unsubstituted primary,         secondary, and tertiary alkyl groups, substituted and         unsubstituted aryl groups, substituted and unsubstituted alkenyl         groups, substituted and unsubstituted alkynyl groups,         substituted and unsubstituted heterocyclyl groups, substituted         and unsubstituted aminoalkyl groups, substituted and         unsubstituted alkylaminoalkyl groups, substituted and         unsubstituted dialkylaminoalkyl groups, substituted and         unsubstituted arylaminoalkyl groups, substituted and         unsubstituted diarylaminoalkyl groups, substituted and         unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and         unsubstituted heterocyclylalkyl groups, and —C(═O)R¹⁸ groups;     -   R⁵, R⁶, R⁷, and R⁸ may be the same or different and are         independently selected from the group consisting of H, Cl, Br,         F, I, —NO₂, —OH, —OR¹⁹ groups, —NR²⁰R²¹ groups, —SH, —SR²²         groups, —S(═O)R²³ groups, —S(═O)₂R²⁴ groups, —CN, substituted         and unsubstituted amidinyl groups, substituted and unsubstituted         guanidinyl groups, substituted and unsubstituted primary,         secondary, and tertiary alkyl groups, substituted and         unsubstituted aryl groups, substituted and unsubstituted alkenyl         groups, substituted and unsubstituted alkynyl groups,         substituted and unsubstituted heterocyclyl groups, substituted         and unsubstituted alkylaminoalkyl groups, substituted and         unsubstituted dialkylaminoalkyl groups, substituted and         unsubstituted arylaminoalkyl groups, substituted and         unsubstituted diarylaminoalkyl groups, substituted and         unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and         unsubstituted heterocyclylalkyl groups, —C(═O)R²⁵ groups,         substituted and unsubstituted aminoalkyl groups, substituted and         unsubstituted heterocyclylaminoalkyl groups, substituted and         unsubstituted hydroxyalkyl groups, substituted and unsubstituted         alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹² is selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, and substituted and unsubstituted heterocyclyl groups;     -   R¹³ is selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, substituted and unsubstituted heterocyclyl groups, —OH,         alkoxy groups, aryloxy groups, —NH₂, substituted and         unsubstituted heterocyclylalkyl groups, substituted and         unsubstituted aminoalkyl groups, substituted and unsubstituted         alkylaminoalkyl groups, substituted and unsubstituted         dialkylaminoalkyl groups, substituted and unsubstituted         arylaminoalkyl groups, substituted and unsubstituted         diarylaminoalkyl groups, substituted and unsubstituted         (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted         alkylamino groups, substituted and unsubstituted arylamino         groups, substituted and unsubstituted dialkylamino groups,         substituted and unsubstituted diarylamino groups, substituted         and unsubstituted (alkyl)(aryl)amino groups, —C(═O)H,         —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups,         —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,         —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂         groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,         —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,         —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl)         groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and         unsubstituted heterocyclylaminoalkyl groups, substituted and         unsubstituted hydroxyalkyl groups, substituted and unsubstituted         alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹⁵ and R¹⁹ may be the same or different and are independently         selected from the group consisting of substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, substituted and unsubstituted heterocyclyl groups,         substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H,         —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,         —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂         groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups,         substituted and unsubstituted aminoalkyl groups, substituted and         unsubstituted alkylaminoalkyl groups, substituted and         unsubstituted dialkylaminoalkyl groups, substituted and         unsubstituted arylaminoalkyl groups, substituted and         unsubstituted diarylaminoalkyl groups, substituted and         unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and         unsubstituted heterocyclylaminoalkyl, substituted and         unsubstituted diheterocyclylaminoalkyl, substituted and         unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted and         unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted and         unsubstituted alkoxyalkyl groups, substituted and unsubstituted         hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹⁶ and R²⁰ may be the same or different and are independently         selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, and substituted and unsubstituted heterocyclyl groups;     -   R¹⁷ and R²¹ may be the same or different and are independently         selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, substituted and unsubstituted heterocyclyl groups,         —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,         —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂         groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups,         —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and         unsubstituted heterocyclylalkyl groups, substituted and         unsubstituted aminoalkyl groups, substituted and unsubstituted         alkylaminoalkyl groups, substituted and unsubstituted         dialkylaminoalkyl groups, substituted and unsubstituted         arylaminoalkyl groups, substituted and unsubstituted         diarylaminoalkyl groups, substituted and unsubstituted         (alkyl)(aryl)aminoalkyl groups, —C(═O)-heterocyclyl groups,         —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,         —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl)         groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and         unsubstituted heterocyclylaminoalkyl groups, substituted and         unsubstituted hydroxyalkyl groups, substituted and unsubstituted         alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹⁸, R²³, R²⁴, and R²⁵ may be the same or different and are         independently selected from the group consisting of H, —NH₂,         —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups,         —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)         groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl)         groups, —N(heterocyclyl)₂ groups, substituted and unsubstituted         alkyl groups, substituted and unsubstituted aryl groups, —OH,         substituted and unsubstituted alkoxy groups, substituted and         unsubstituted aryloxy groups, substituted and unsubstituted         heterocyclyl groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH         groups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups,         —N(alkyl)O-aryl groups, and —N(aryl)O-aryl groups; and     -   R²² is selected from the group consisting of substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, and substituted and unsubstituted heterocyclyl groups.

Further objects, features and advantages of the invention will be apparent from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effects of various amount of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1) on a 4T1 murine breast tumor model (vehicle (grey outlined circle); 10 mpk (square); 30 mpk (grey triangle); 60 mpk (X); 100 mpk (diamond); and 150 mpk (filed circle)). The growth of the subcutaneous tumor was inhibited (40-80% compared to control), liver metastases were completely inhibited, and lung metastases were inhibited by 60-97% after 18 days of dosing.

FIGS. 2A and 2B are graphs showing the dose-dependent reduction of soluble ICAM (FIG. 2A; greater than 70% inhibition with 100 or 150 mg/kg) and soluble VCAM (FIG. 2B; 44-47% inhibition with 100 or 150 mg/kg) in the serum of mice with 4T1 breast tumors when dosed with varying amounts of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one.

FIG. 3 is a graph showing the dose-dependent inhibition of mouse-specific soluble E-selectin in the serum of 4T1 tumor bearing mice treated with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one.

FIGS. 4A, 4B, and 4C are graphs of the Zymography and VEGF ELISA (FIG. 4B) data that show the decrease in MMP9 and VEGF in mice with implanted KM12L4a tumor cells when dosed for 7 days with 100 mg/kg 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one.

FIG. 5 is a scanned image showing the decrease in the expression of ICAM, and VCAM when HUVECs in culture were treated with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H).

FIG. 6 is a scanned image showing the decrease in the expression of α5 integrin, not αv integrin when HUVECs in culture were treated with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H).

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations and definitions are used throughout this application:

The phrase “cellular adhesion” as used herein, refers to cell adhesion. The amount of cellular adhesion in a subject can typically be correlated with the amounts of cell adhesion molecules, such as, but not limited to VCAM, ICAM, and E-Selectin in a subject.

“VCAM” is an abbreviation that stands for vascular cell adhesion molecule.

“ICAM” is an abbreviation that stands for inducible cell adhesion molecule.

“E-Selectin” is also known as endothelial leukocyte adhesion molecule.

“4T1” is a murine breast cell line.

“BALB/C” is a mice strain used in tumor xenograph experiments.

“bFGF” is an abbreviation that stands for basic fibroblast growth factor.

“FGFR1”, also referred to as bFGFR, is an abbreviation that stands for a tyrosine kinase that interacts with the fibroblast growth factor FGF.

“FGF” is an abbreviation for the fibroblast growth factor that interacts with FGFR1.

“FGFR3” is an abbreviation that stands for the tyrosine kinase fibroblast growth factor receptor 3 that is often expressed in multiple myeloma-type cancers.

“Flk-1” is an abbreviation that stands for fetal liver tyrosine kinase 1, also known as kinase-insert domain tyrosine kinase or KDR (human), also known as vascular endothelial growth factor receptor-2 or VEGFR2 (KDR (human), Flk-1 (mouse)).

“PDGF” is an abbreviation that stands for platelet derived growth factor. PDGF interacts with tyrosine kinases PDGFRα and PDGFRβ.

“RTK” is an abbreviation that stands for receptor tyrosine kinase.

“VEGF” is an abbreviation that stands for vascular endothelial growth factor.

“VEGF-RTK” is an abbreviation that stands for vascular endothelial growth factor receptor tyrosine kinase.

“ELISA” is an abbreviation that stands for Enzyme-Linked Immunosorbent Assay.

“MMP-2” is an abbreviation that stands for matrix metalloprotease-2 [includes the 72 KD (pro MMP-2) protein and the 62 KD (active MMP-2) protein]. MMP-2 is also referred to as gelatinase A.

“MMP-9” is an abbreviation that stands for matrix metalloprotease-9 [includes the 105 KD (pro MMP-9) protein and the 92 KD (active MMP-9) protein]. MMP-9 is also referred to as gelatinase B.

“Ki67” is a marker for cellular proliferation.

“Caspase-3” is a apoptosis marker. Activation of caspase-3 requires proteolytic processing of inactive caspase-3 into “cleaved caspase-3” which is 17 KD and 19 KD in size.

“PARP” is an abbreviation that stands for poly ADP-ribose polymerase and is an apoptosis marker. It is a 116 KD protein and is cleaved into a 89 KD protein.

“CD31” is a marker for endothelial cells. Immunostaining with anti-CD31 antibody in tumor section by immunohistochemistry will indicate the number of microvessels (or microvessel density) in tumors.

Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium.

The phrase “unsubstituted alkyl” refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃, —C(CH₂CH₃)₃, —CH₂CH(CH₃)₂, —CH₂CH(CH₃)(CH₂CH₃), —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH₂C(CH₂CH₃)₃, —CH(CH₃)CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃), —CH₂CH₂CH(CH₂CH₃)₂, —CH₂CH₂C(CH₃)₃, —CH₂CH₂C(CH₂CH₃)₃, —CH(CH₃)CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)CH(CH₃)₂, —CH(CH₂CH₃)CH(CH₃)CH(CH₃)(CH₂CH₃), and others. The phrase also includes cyclic alkyl groups such as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus, the phrase unsubstituted alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. Preferred unsubstituted alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms. More preferred such unsubstituted alkyl groups have from 1 to 10 carbon atoms while even more preferred such groups have from 1 to 5 carbon atoms. Most preferred unsubstituted alkyl groups include straight and branched chain alkyl groups having from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and —CH(CH₃)₂.

The phrase “substituted alkyl” refers to an unsubstituted alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom in halides such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms. One example of a substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group. Other alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, aryloxy group, or heterocyclyloxy group. Still other alkyl groups include alkyl groups that have an amine, alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine, or diheterocyclylamine group.

The phrase “unsubstituted aryl” refers to aryl groups that do not contain heteroatoms. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example. Although the phrase “unsubstituted aryl” includes groups containing condensed rings such as naphthalene, it does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described below. A preferred unsubstituted aryl group is phenyl. Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound, however.

The phrase “substituted aryl group” has the same meaning with respect to unsubstituted aryl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. However, a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (e.g. dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase “substituted aryl” includes, but is not limited to tolyl, and hydroxyphenyl among others.

The phrase “unsubstituted alkenyl” refers to straight and branched chain and cyclic groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to vinyl, —CH═C(H)(CH₃), —CH═C(CH₃)₂, —C(CH₃)═C(H)₂, —C(CH₃)═C(H)(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

The phrase “substituted alkenyl” has the same meaning with respect to unsubstituted alkenyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.

The phrase “unsubstituted alkynyl” refers to straight and branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to —C≡C(H), —C≡C(CH₃), —C≡C(CH₂CH₃), —C(H₂)C≡C(H), —C(H)₂C≡C(CH₃), and —C(H)₂C≡C(CH₂CH₃) among others.

The phrase “substituted alkynyl” has the same meaning with respect to unsubstituted alkynyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.

The phrase “unsubstituted aralkyl” refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to an aryl group as defined above. For example, methyl(—CH₃) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a phenyl group, such as if the carbon of the methyl were bonded to a carbon of benzene, then the compound is an unsubstituted aralkyl group (i.e., a benzyl group). Thus the phrase includes, but is not limited to, groups such as benzyl, diphenylmethyl, and 1-phenylethyl(—CH(C₆H₅)(CH₃)) among others.

The phrase “substituted aralkyl” has the same meaning with respect to unsubstituted aralkyl groups that substituted aryl groups had with respect to unsubstituted aryl groups. However, a substituted aralkyl group also includes groups in which a carbon or hydrogen bond of the alkyl part of the group is replaced by a bond to a non-carbon or a non-hydrogen atom. Examples of substituted aralkyl groups include, but are not limited to, —CH₂C(═O)(C₆H₅), and —CH₂(2-methylphenyl) among others.

The phrase “unsubstituted heterocyclyl” refers to both aromatic and nonaromatic ring compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, quinuclidyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S. Although the phrase “unsubstituted heterocyclyl” includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples of heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g. 2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g., 2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered rings containing oxygen atoms such as, but not limited to furyl; unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms such as benzodioxolyl (e.g., 1,3-benzodioxoyl, etc.); unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl group also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene oxide and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5 or 6 ring members. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.

The phrase “substituted heterocyclyl” refers to an unsubstituted heterocyclyl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, N-alkyl piperazinyl groups such as 1-methyl piperazinyl, piperazine-N-oxide, N-alkyl piperazine N-oxides, 2-phenoxy-thiophene, and 2-chloropyridinyl among others. In addition, substituted heterocyclyl groups also include heterocyclyl groups in which the bond to the non-hydrogen atom is a bond to a carbon atom that is part of a substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, or unsubstituted heterocyclyl group. Examples include but are not limited to 1-benzylpiperidinyl, 3-phenylhiomorpholinyl, 3-(pyrrolidin-1-yl)-pyrrolidinyl, and 4-(piperidin-1-yl)-piperidinyl. Groups such as N-alkyl substituted piperazine groups such as N-methyl piperazine, substituted morpholine groups, and piperazine N-oxide groups such as piperazine N-oxide and N-alkyl piperazine N-oxides are examples of some substituted heterocyclyl groups. Groups such as substituted piperazine groups such as N-alkyl substituted piperazine groups such as N-methyl piperazine and the like, substituted morpholine groups, piperazine N-oxide groups, and N-alkyl piperazine N-oxide groups are examples of some substituted heterocyclyl groups that are especially suited as R⁶ or R⁷ groups.

The phrase “unsubstituted heterocyclylalkyl” refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl group as defined above. For example, methyl(—CH₃) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a heterocyclyl group, such as if the carbon of the methyl were bonded to carbon 2 of pyridine (one of the carbons bonded to the N of the pyridine) or carbons 3 or 4 of the pyridine, then the compound is an unsubstituted heterocyclylalkyl group.

The phrase “substituted heterocyclylalkyl” has the same meaning with respect to unsubstituted heterocyclylalkyl groups that substituted aralkyl groups had with respect to unsubstituted aralkyl groups. However, a substituted heterocyclylalkyl group also includes groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylalkyl group. In addition, a substituted heterocyclylalkyl group also includes groups in which a carbon bond or a hydrogen bond of the alkyl part of the group is replaced by a bond to a substituted and unsubstituted aryl or substituted and unsubstituted aralkyl group. Examples include but are not limited to phenyl-(piperidin-1-yl)-methyl and phenyl-(morpholin-4-yl)-methyl.

The phrase “unsubstituted alkylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an unsubstituted alkyl group as defined above. For example, methyl(—CH₃) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an ethyl group, then the resulting compound is —CH₂—N(H)(CH₂CH₃) which is an unsubstituted alkylaminoalkyl group.

The phrase “substituted alkylaminoalkyl” refers to an unsubstituted alkylaminoalkyl group as defined above except where one or more bonds to a carbon or hydrogen atom in one or both of the alkyl groups is replaced by a bond to a non-carbon or non-hydrogen atom as described above with respect to substituted alkyl groups except that the bond to the nitrogen atom in all alkylaminoalkyl groups does not by itself qualify all alkylaminoalkyl groups as being substituted. However, substituted alkylaminoalkyl groups does include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.

The phrase “unsubstituted dialkylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to two other similar or different unsubstituted alkyl groups as defined above.

The phrase “substituted dialkylaminoalkyl” refers to an unsubstituted dialkylaminoalkyl group as defined above in which one or more bonds to a carbon or hydrogen atom in one or more of the alkyl groups is replaced by a bond to a non-carbon and non-hydrogen atom as described with respect to substituted alkyl groups. The bond to the nitrogen atom in all dialkylaminoalkyl groups does not by itself qualify all dialkylaminoalkyl groups as being substituted.

The phrase “unsubstituted alkoxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an otherwise unsubstituted alkyl group as defined above.

The phrase “substituted alkoxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an otherwise substituted alkyl group as defined above.

The phrase “unsubstituted heterocyclyloxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of an otherwise unsubstituted heterocyclyl group as defined above.

The phrase “substituted heterocyclyloxy” refers to a hydroxyl group (—OH) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of an otherwise substituted heterocyclyl group as defined above.

The phrase “unsubstituted heterocyclyloxyalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to an unsubstituted heterocyclyl group as defined above.

The phrase “substituted heterocyclyloxyalkyl” refers to an unsubstituted heterocyclyloxyalkyl group as defined above in which a bond to a carbon or hydrogen group of the alkyl group of the heterocyclyloxyalkyl group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups or in which the heterocyclyl group of the heterocyclyloxyalkyl group is a substituted heterocyclyl group as defined above.

The phrase “unsubstituted heterocyclylalkoxy” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound, and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to an unsubstituted heterocyclyl group as defined above.

The phrase “substituted heterocyclylalkoxy” refers to an unsubstituted heterocyclylalkoxy group as defined above in which a bond to a carbon or hydrogen group of the alkyl group of the heterocyclylalkoxy group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups or in which the heterocyclyl group of the heterocyclylalkoxy group is a substituted heterocyclyl group as defined above. Further, a substituted heterocyclylalkoxy group also includes groups in which a carbon bond or a hydrogen bond to the alkyl moiety of the group may be substituted with one or more additional substituted and unsubstituted heterocycles. Examples include but are not limited to pyrid-2-ylmorpholin-4-ylmethyl and 2-pyrid-3-yl-2-morpholin-4-ylethyl.

The phrase “unsubstituted arylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to at least one unsubstituted aryl group as defined above.

The phrase “substituted arylaminoalkyl” refers to an unsubstituted arylaminoalkyl group as defined above except where either the alkyl group of the arylaminoalkyl group is a substituted alkyl group as defined above or the aryl group of the arylaminoalkyl group is a substituted aryl group except that the bonds to the nitrogen atom in all arylaminoalkyl groups does not by itself qualify all arylaminoalkyl groups as being substituted. However, substituted arylaminoalkyl groups does include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.

The phrase “unsubstituted heterocyclylaminoalkyl” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to at least one unsubstituted heterocyclyl group as defined above.

The phrase “substituted heterocyclylaminoalkyl” refers to unsubstituted heterocyclylaminoalkyl groups as defined above in which the heterocyclyl group is a substituted heterocyclyl group as defined above and/or the alkyl group is a substituted alkyl group as defined above. The bonds to the nitrogen atom in all heterocyclylaminoalkyl groups does not by itself qualify all heterocyclylaminoalkyl groups as being substituted. However, substituted heterocyclylaminoalkyl groups do include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.

The phrase “unsubstituted alkylaminoalkoxy” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom which is bonded to a hydrogen atom and an unsubstituted alkyl group as defined above.

The phrase “substituted alkylaminoalkoxy” refers to unsubstituted alkylaminoalkoxy groups as defined above in which a bond to a carbon or hydrogen atom of the alkyl group bonded to the oxygen atom which is bonded to the parent compound is replaced by one or more bonds to a non-carbon and non-hydrogen atoms as discussed above with respect to substituted alkyl groups and/or if the hydrogen bonded to the amino group is bonded to a non-carbon and non-hydrogen atom and/or if the alkyl group bonded to the nitrogen of the amine is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all alkylaminoalkoxy groups does not by itself qualify all such groups as substituted alkylaminoalkoxy groups.

The phrase “unsubstituted dialkylaminoalkoxy” refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom which is bonded to two other similar or different unsubstituted alkyl groups as defined above.

The phrase “substituted dialkylaminoalkoxy” refers to an unsubstituted dialkylaminoalkoxy group as defined above in which a bond to a carbon or hydrogen atom of the alkyl group bonded to the oxygen atom which is bonded to the parent compound is replaced by one or more bonds to a non-carbon and non-hydrogen atoms as discussed above with respect to substituted alkyl groups and/or if one or more of the alkyl groups bonded to the nitrogen of the amine is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all dialkylaminoalkoxy groups does not by itself qualify all such groups as substituted dialkylaminoalkoxy groups.

The term “protected” with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoroacetate. Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.

A “pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

In one aspect, the invention provides a method of modulating an inflammatory response and/or reducing cellular adhesion in a subject. Such methods include administering to the subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The inflammatory response is modulated in the subject and/or cellular adhesion is reduced in the subject after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.

In one embodiment, the invention provides a method of treating a disorder related to inflammation in a human or animal subject. The method includes administering to the human or animal subject an effective amount of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. Inflammation and inflammatory responses may occur with various biological conditions. Examples of such biological conditions may include cancer, autoimmune diseases, asthma, allergies, eczema, microbial infections, traumatic injuries such as burns or cuts, lupus, arthritis, cardiovascular disease such as, but not limited to, strokes and ischemic injuries, respiratory bacterial and viral infections, and other conditions associated with inflammatory responses.

In another embodiment, the invention provides a method of treating a disorder related to cellular adhesion in a human or animal subject. The method includes administering to the human or animal subject an effective amount of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof.

In another embodiment, the invention provides a method of decreasing cellular adhesion molecules such as ICAM, VCAM, E-selectin, MMP-2, or MMP-9 levels in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The amount of the cellular adhesion molecule is typically reduced in the subject after administration.

In another embodiment, the invention provides a method of decreasing circulating ICAM, VCAM, E-selectin, MMP-2, or MMP-9 levels in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof.

In another embodiment, the invention provides a method of decreasing circulating cell adhesion molecules in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof.

In yet another embodiment, the invention provides a method of monitoring the progression of a disease or treatment in a human or animal subject. The method includes administering to the human or animal subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof and measuring the amounts of a molecule such as ICAM, VCAM, E-selectin, MMP-2, or MMP-9 levels in the subject.

In another aspect, the invention provides a method of monitoring the progression of a disease or treatment in a human or animal subject. The method includes measuring the amount of at least one cell adhesion molecule in the subject after administration of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-Selectin). Some such methods further include withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample.

In another aspect, the invention provides a method of identifying a subject in need of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof. The method includes measuring the amount of at least one cell adhesion molecule in the subject before, during, or after administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule. In some embodiments, the cell adhesion molecule is selected from inducible cell adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), or endothelial leukocyte adhesion molecule (E-Selectin). Some such methods further include withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample.

In some embodiments of any of the methods described herein, the subject is a cancer patient.

Structure I has the following formula:

-   -   wherein,     -   R¹, R², R³, and R⁴ may be the same or different and are         independently selected from the group consisting of H, Cl, Br,         F, I, —CN, —NO₂, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷ groups, substituted         and unsubstituted amidinyl groups, substituted and unsubstituted         guanidinyl groups, substituted and unsubstituted primary,         secondary, and tertiary alkyl groups, substituted and         unsubstituted aryl groups, substituted and unsubstituted alkenyl         groups, substituted and unsubstituted alkynyl groups,         substituted and unsubstituted heterocyclyl groups, substituted         and unsubstituted aminoalkyl groups, substituted and         unsubstituted alkylaminoalkyl groups, substituted and         unsubstituted dialkylaminoalkyl groups, substituted and         unsubstituted arylaminoalkyl groups, substituted and         unsubstituted diarylaminoalkyl groups, substituted and         unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and         unsubstituted heterocyclylalkyl groups, and —C(═O)R¹⁸ groups;     -   R⁵, R⁶, R⁷, and R⁸ may be the same or different and are         independently selected from the group consisting of H, Cl, Br,         F, I, —NO₂, —OH, —OR¹⁹ groups, —NR²⁰R²¹ groups, —SH, —SR²²         groups, —S(═O)R²³ groups, —S(═O)₂R²⁴ groups, —CN, substituted         and unsubstituted amidinyl groups, substituted and unsubstituted         guanidinyl groups, substituted and unsubstituted primary,         secondary, and tertiary alkyl groups, substituted and         unsubstituted aryl groups, substituted and unsubstituted alkenyl         groups, substituted and unsubstituted alkynyl groups,         substituted and unsubstituted heterocyclyl groups, substituted         and unsubstituted alkylaminoalkyl groups, substituted and         unsubstituted dialkylaminoalkyl groups, substituted and         unsubstituted arylaminoalkyl groups, substituted and         unsubstituted diarylaminoalkyl groups, substituted and         unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and         unsubstituted heterocyclylalkyl groups, —C(═O)R²⁵ groups,         substituted and unsubstituted aminoalkyl groups, substituted and         unsubstituted heterocyclylaminoalkyl groups, substituted and         unsubstituted hydroxyalkyl groups, substituted and unsubstituted         alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹² is selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, and substituted and unsubstituted heterocyclyl groups;     -   R¹³ is selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, substituted and unsubstituted heterocyclyl groups, —OH,         alkoxy groups, aryloxy groups, —NH₂, substituted and         unsubstituted heterocyclylalkyl groups, substituted and         unsubstituted aminoalkyl groups, substituted and unsubstituted         alkylaminoalkyl groups, substituted and unsubstituted         dialkylaminoalkyl groups, substituted and unsubstituted         arylaminoalkyl groups, substituted and unsubstituted         diarylaminoalkyl groups, substituted and unsubstituted         (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted         alkylamino groups, substituted and unsubstituted arylamino         groups, substituted and unsubstituted dialkylamino groups,         substituted and unsubstituted diarylamino groups, substituted         and unsubstituted (alkyl)(aryl)amino groups, —C(═O)H,         —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups,         —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups,         —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂         groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups,         —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,         —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl)         groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and         unsubstituted heterocyclylaminoalkyl groups, substituted and         unsubstituted hydroxyalkyl groups, substituted and unsubstituted         alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹⁵ and R¹⁹ may be the same or different and are independently         selected from the group consisting of substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, substituted and unsubstituted heterocyclyl groups,         substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H,         —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,         —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂         groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups,         substituted and unsubstituted aminoalkyl groups, substituted and         unsubstituted alkylaminoalkyl groups, substituted and         unsubstituted dialkylaminoalkyl groups, substituted and         unsubstituted arylaminoalkyl groups, substituted and         unsubstituted diarylaminoalkyl groups, substituted and         unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and         unsubstituted heterocyclylaminoalkyl, substituted and         unsubstituted diheterocyclylaminoalkyl, substituted and         unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted and         unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted and         unsubstituted alkoxyalkyl groups, substituted and unsubstituted         hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹⁶ and R²⁰ may be the same or different and are independently         selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, and substituted and unsubstituted heterocyclyl groups;     -   R¹⁷ and R²¹ may be the same or different and are independently         selected from the group consisting of H, substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, substituted and unsubstituted heterocyclyl groups,         —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂,         —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂         groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups,         —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and         unsubstituted heterocyclylalkyl groups, substituted and         unsubstituted aminoalkyl groups, substituted and unsubstituted         alkylaminoalkyl groups, substituted and unsubstituted         dialkylaminoalkyl groups, substituted and unsubstituted         arylaminoalkyl groups, substituted and unsubstituted         diarylaminoalkyl groups, substituted and unsubstituted         (alkyl)(aryl)aminoalkyl groups, —C(═O)-heterocyclyl groups,         —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups,         —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl)         groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and         unsubstituted heterocyclylaminoalkyl groups, substituted and         unsubstituted hydroxyalkyl groups, substituted and unsubstituted         alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl         groups, and substituted and unsubstituted heterocyclyloxyalkyl         groups;     -   R¹⁸, R²³, R²⁴, and R²⁵ may be the same or different and are         independently selected from the group consisting of H, —NH₂,         —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups,         —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl)         groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl)         groups, —N(heterocyclyl)₂ groups, substituted and unsubstituted         alkyl groups, substituted and unsubstituted aryl groups, —OH,         substituted and unsubstituted alkoxy groups, substituted and         unsubstituted aryloxy groups, substituted and unsubstituted         heterocyclyl groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH         groups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups,         —N(alkyl)O-aryl groups, and —N(aryl)O-aryl groups; and     -   R²² is selected from the group consisting of substituted and         unsubstituted alkyl groups, substituted and unsubstituted aryl         groups, and substituted and unsubstituted heterocyclyl groups.

In some embodiments of the pharmaceutically acceptable salts of the compounds or the tautomers of the compounds of Structure I, at least one of R⁵, R⁶, R⁷, or R⁸ is selected from the group consisting of substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted saturated heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; —OR¹⁹ groups wherein R¹⁹ is selected from the group consisting of substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; —NR²⁰R²¹ groups wherein R²⁰ is selected from the group consisting of substituted and unsubstituted heterocyclyl groups; —NR²⁰R²¹ groups wherein R²¹ is selected from the group consisting of substituted and unsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; and —C(═O)R²⁵ groups wherein R²⁵ is selected from the group consisting of H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, substituted and unsubstituted aryl groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted heterocyclyl groups.

In one embodiment, the invention relates to a pharmaceutically acceptable salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1) or a tautomer thereof. In some such embodiments, the salt is selected from the group consisting of tartrate, malate, lactate, bis-acetate, citrate, mesylate, bismesylate and bishydrochloride.

In some specific embodiments, the compound of structure I is a lactate salt of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one or a tautomer thereof.

In some specific embodiments, the pharmaceutically acceptable salt of the compound of Structure I, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.

In some embodiments, at least one of R¹² and R¹³ is H, and in other embodiments, both R¹² and R¹³ are H.

In a some embodiments, R¹ is selected from the group consisting of F, Cl, substituted and unsubstituted alkoxy groups, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkoxy groups, substituted and unsubstituted arylaminoalkoxy groups, substituted and unsubstituted dialkylaminoalkoxy groups, substituted and unsubstituted diarylaminoalkoxy groups, and substituted and unsubstituted (alkyl)(aryl)aminoalkoxy groups.

In some embodiments, R¹ is F and R², R³, R³, R⁴, R⁵, and R⁸ are all H, and one of R⁶ or R⁷ is H.

In some other embodiments, at least one of R⁵, R⁶, R⁷, and R⁸ is a substituted or unsubstituted heterocyclyl group.

In still other embodiments, at least one of R⁵, R⁶, R⁷, and R⁸ is a substituted or unsubstituted heterocyclyl group comprising at least one O or N atom.

In yet other embodiments, at least one of R⁵, R⁶, R⁷, and R⁸ is a substituted or unsubstituted heterocyclyl group and the heterocyclyl group is selected from the group consisting of morpholine, piperazine, piperidine, pyrrolidine, thiomorpholine, homopiperazine, tetrahydrothiophene, tetrahydrofuran, and tetrahydropyran.

In yet other embodiments, at least one of R⁶ or R⁷ is a substituted or unsubstituted heterocyclyl group.

In yet other embodiments, at least one of R⁶ or R⁷ is a substituted or unsubstituted heterocyclyl group comprising at least one O or N atom.

In yet other embodiments, one of R⁶ or R⁷ is a substituted or unsubstituted heterocyclyl group and the heterocyclyl group is selected from the group consisting of morpholine, piperazine, piperidine, pyrrolidine, thiomorpholine, homopiperazine, tetrahydrothiophene, tetrahydrofuran, and tetrahydropyran.

In still other particular embodiments, one of R⁶ or R⁷ is selected from the group consisting of substituted and unsubstituted morpholine groups, and substituted and unsubstituted piperazine groups. In some such embodiments, one of R⁶ or R⁷ is a piperazine N-oxide or is an N-alkyl substituted piperazine.

In yet other embodiments, at least one of and in some embodiments one of R⁶ or R⁷ is selected from the group consisting of —NR²⁰R²¹ groups wherein R²⁰ is selected from the group consisting of substituted and unsubstituted heterocyclyl groups; and —NR²⁰R²¹ groups wherein R²¹ is selected from the group consisting of substituted and unsubstituted heterocyclyl groups, groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups.

In yet another embodiment, R¹ is selected from the group consisting of H and F.

In yet another embodiment, the compounds and their corresponding salts and tautomers are provided in the following two tables below. The synthesis of these compounds is described in U.S. Pat. No. 6,605,617, published U.S. Patent Application No. 2004/0092535, published U.S. Patent Application No. 2004/0220196 as are various kinase assay procedures. Each of these references is, therefore, hereby incorporated by reference in its entirety and for all purposes as if set forth in its entirety. TABLE of Exemplary Compounds LC/MS m/z Example Name (MH+) 1 4-amino-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 389.4 benzimidazol-2-yl}quinolin-2(1H)-one 2 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 420 yl)-6-chloroquinolin-2(1H)-one 3 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 420 yl)-6-chloroquinolin-2(1H)-one 4 3-(1H-benzimidazol-2-yl)-4-[(3R)-3-(dimethylamino)pyrrolidin-1- 374.2 yl]quinolin-2(1H)-one 5 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(3R)-3- 408.1 (dimethylamino)pyrrolidin-1-yl]quinolin-2(1H)-one 6 4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1- 403.2 methylquinolin-2(1H)-one 7 4-amino-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)quinolin- 361.2 2(1H)-one 8 4-amino-3-[6-(pyridin-4-ylmethyl)-1H-benzimidazol-2- 368.2 yl]quinolin-2(1H)-one 9 4-amino-3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H- 389.4 benzimidazol-2-yl}quinolin-2(1H)-one 10 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 375.2 yl]quinolin-2(1H)-one 11 4-amino-3-(6-methyl-5-morpholin-4-yl-1H-benzimidazol-2- 376 yl)quinolin-2(1H)-one 12 4-amino-3-{5-[(1-methylpiperidin-3-yl)oxy]-1H-benzimidazol-2- 390.1 yl}quinolin-2(1H)-one 13 4-amino-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-fluoro-1H- 408.2 benzimidazol-2-yl}quinolin-2(1H)-one 14 4-amino-3-{5-[(1-methylpyrrolidin-3-yl)oxy]-1H-benzimidazol-2- 376.2 yl}quinolin-2(1H)-one 15 4-amino-3-[5-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2- 389.2 yl]quinolin-2(1H)-one 16 4-amino-3-{5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 389.2 benzimidazol-2-yl}quinolin-2(1H)-one 17 4-amino-6-chloro-3-{5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]- 423 1H-benzimidazol-2-yl}quinolin-2(1H)-one 18 ethyl {4-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 447.2 benzimidazol-6-yl]piperazin-1-yl}acetate 19 4-amino-3-{6-[methyl(1-methylpiperidin-4-yl)amino]-1H- 403.1 benzimidazol-2-yl}quinolin-2(1H)-one 20 3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 403.3 aminoquinolin-2(1H)-one 21 4-amino-3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2- 443.3 yl]quinolin-2(1H)-one 22 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-be-nzimidazole- 321.2 6-carboxylic acid 23 4-amino-5-(methyloxy)-3-[6-(4-methylpiperazin-1-yl)-1H- 405.3 benzimidazol-2-yl]quinolin-2(1H)-one 24 4-amino-3-{6-[4-(1-methylethyl)piperazin-1-yl]-1H-benzimidazol- 403.3 2-yl}quinolin-2(1H)-one 25 {4-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 419.2 benzimidazol-6-yl]piperazin-1-yl}acetic acid 26 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 386.1 yl)quinolin-2(1H)-one 27 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 386.1 yl)quinolin-2(1H)-one 28 4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2- 389.1 yl]quinolin-2(1H)-one 29 4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5- 433.3 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)-one 30 4-amino-6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol- 409.2 2-yl]quinolin-2(1H)-one 31 4-amino-6-chloro-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]- 423.1 1H-benzimidazol-2-yl}quinolin-2(1H)-one 32 4-amino-5,6-dichloro-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1- 457.2 yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one 33 4-amino-5,6-dichloro-3-[5-(4-methylpiperazin-1-yl)-1H- 443.2 benzimidazol-2-yl]quinolin-2(1H)-one 34 4-amino-3-(1H-benzimidazol-2-yl)-6-[(pyridin-2- 384.2 ylmethyl)oxy]quinolin-2(1H)-one 35 4-amino-3-(1H-benzimidazol-2-yl)-6-[(2R,6S)-2,6- 390.1 dimethylmorpholin-4-yl]quinolin-2(1H)-one 36 4-amino-3-(1H-benzimidazol-2-yl)-6-morpholin-4-ylquinolin- 362.2 2(1H)-one 37 4-amino-3-(1H-benzimidazol-2-yl)-5-[(1-methylpiperidin-3- 390.2 yl)oxy]quinolin-2(1H)-one 38 4-amino-3-(1H-benzimidazol-2-yl)-5-[(pyridin-2- 384.1 ylmethyl)oxy]quinolin-2(1H)-one 39 4-amino-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-5-[(pyridin- 469.2 4-ylmethyl)oxy]quinolin-2(1H)-one 40 4-amino-3-(1H-benzimidazol-2-yl)-5-(methyloxy)quinolin-2(1H)- 307.1 one 41 4-amino-3-(5-methyl-1H-benzimidazol-2-yl)-5- 321.1 (methyloxy)quinolin-2(1H)-one 42 4-amino-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H- 420.2 benzimidazol-2-yl}-5-(methyloxy)quinolin-2(1H)-one 43 4-amino-3-(1H-benzimidazol-2-yl)-5-morpholin-4-ylquinolin- 362.2 2(1H)-one 44 4-amino-3-(1H-benzimidazol-2-yl)-5-[(2R,6S)-2,6- 390.2 dimethylmorpholin-4-yl]quinolin-2(1H)-one 45 4-amino-3-(1H-benzimidazol-2-yl)-5-(4-methylpiperazin-1- 375.1 yl)quinolin-2(1H)-one 46 4-amino-5,6-dichloro-3-(5-morpholin-4-yl-1H-benzimidazol-2- 430 yl)quinolin-2(1H)-one 47 3-{5-[(2-morpholin-4-ylethyl)oxy]-1H-benzimidazol-2- 391.3 yl}quinolin-2(1H)-one 48 4-amino-3-{5-[(3-pyrrolidin-1-ylpropyl)oxy]-1H-benzimidazol-2- 404 yl}quinolin-2(1H)-one 49 4-amino-3-{5-[(3-morpholin-4-ylpropyl)oxy]-1H-benzimidazol-2- 420.4 yl}quinolin-2(1H)-one 50 4-amino-6-fluoro-3-(5-morpholin-4-yl-1H-benzimidazol-2- 380 yl)quinolin-2(1H)-one 51 4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H- 407 benzimidazol-2-yl}-6-fluoroquinolin-2(1H)-one 52 4-amino-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one 295 53 4-amino-3-(6-fluoro-5-morpholin-4-yl-1H-benzimidazol-2- 380 yl)quinolin-2(1H)-one 54 4-amino-3-{5-[(tetrahydrofuran-2-ylmethyl)oxy]-1H- 377 benzimidazol-2-yl}quinolin-2(1H)-one 55 4-amino-6-fluoro-3-(6-fluoro-5-morpholin-4-yl-1H-benzimidazol- 398 2-yl)quinolin-2(1H)-one 56 4-amino-3-[6-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazol- 393 2-yl]quinolin-2(1H)-one 57 4-amino-3-(5-{[2-(methyloxy)ethyl]oxy}-1H-benzimidazol-2- 351 yl)quinolin-2(1H)-one 58 4-amino-3-[4,6-difluoro-5-(4-methylpiperazin-1-yl)-1H- 411 benzimidazol-2-yl]quinolin-2(1H)-one 59 4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H- 407.1 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 60 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol- 393.1 2-yl]quinolin-2(1H)-one 61 4-amino-5-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol- 409.1 2-yl]quinolin-2(1H)-one 62 4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-6-fluoro-1H- 407.1 benzimidazol-2-yl}quinolin-2(1H)-one 63 4-amino-5-chloro-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H- 423.1 benzimidazol-2-yl}quinolin-2(1H)-one 64 4-amino-6-chloro-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-6- 441 fluoro-1H-benzimidazol-2-yl}quinolin-2(1H)-one 65 4-amino-5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-(3H- 391.2 imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one 66 4-amino-3-(6-thiomorpholin-4-yl-1H-benzimidazol-2-yl)quinolin- 378.4 2(1H)-one 67 4-amino-3-[5-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2- 443.1 yl]quinolin-2(1H)-one 68 4-amino-3-{6-[3-(diethylamino)pyrrolidin-1-yl]-1H-benzimidazol- 417.1 2-yl}quinolin-2(1H)-one 69 4-amino-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzimidazol-2- 438.3 yl]quinolin-2(1H)-one 70 4-amino-3-[5-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridin- 376.3 2-yl]quinolin-2(1H)-one 71 4-amino-6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-imidazo[4,5- 410.2 b]pyridin-2-yl]quinolin-2(1H)-one 72 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-N-(1- 431.3 methylpiperidin-4-yl)-1H-benzimidazole-5-carboxamide 73 4-amino-3-(5-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}-1H- 431.3 benzimidazol-2-yl)quinolin-2(1H)-one 74 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 420.2 nitroquinolin-2(1H)-one 75 4-amino-3-[5-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol-2- 471.1 yl]quinolin-2(1H)-one 76 4-amino-3-{5-[(4-methylpiperazin-1-yl)carbonyl]-1H- 403.3 benzimidazol-2-yl}quinolin-2(1H)-one 77 4-amino-3-[5-(1-oxidothiomorpholin-4-yl)-1H-benzimidazol-2- 394.5 yl]quinolin-2(1H)-one 78 3-{5-[(4-acetylpiperazin-1-yl)carbonyl]-1H-benzimidazol-2-yl}-4- 431.3 aminoquinolin-2(1H)-one 79 4-amino-3-(5-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}- 417.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 80 4-amino-3-(5-{[(3S)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}- 417.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 81 4-amino-3-(5-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-1H- 431.4 benzimidazol-2-yl)quinolin-2(1H)-one 82 methyl 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 353.2 benzimidazole-6-carboxylate 83 4-amino-3-[5-(1,3′-bipyrrolidin-1′-yl)-1H-benzimidazol-2- 415.5 yl]quinolin-2(1H)-one 84 4-amino-3-[5-(pyridin-3-yloxy)-1H-benzimidazol-2-yl]quinolin- 370.2 2(1H)-one 85 4-amino-5,6-bis(methyloxy)-3-[5-(4-methylpiperazin-1-yl)-1H- 435.5 benzimidazol-2-yl]quinolin-2(1H)-one 86 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[2- 405.3 (dimethylamino)ethyl]-N-methyl-1H-benzimidazole-5- carboxamide 87 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl-N-(1- 417.2 methylpyrrolidin-3-yl)-1H-benzimidazole-5-carboxamide 88 4-amino-3-{5-[(5-methyl-2,5-diazabicyclo[2.2.1]hept-2- 415.2 yl)carbonyl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one 89 4-amino-3-{5-[(4-cyclohexylpiperazin-1-yl)carbonyl]-1H- 471.6 benzimidazol-2-yl}quinolin-2(1H)-one 90 4-amino-3-{5-[(2-piperidin-1-ylethyl)amino]-1H-benzimidazol-2- 403.2 yl}quinolin-2(1H)-one 91 ethyl 4-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 447.3 benzimidazol-5-yl]amino}piperidine-1-carboxylate 92 4-amino-3-[5-({(5R)-5-[(methyloxy)methyl]pyrrolidin-3- 405.2 yl}amino)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 93 4-amino-3-{5-[(pyridin-2-ylmethyl)aminol]-1H-benzimidazol-2- 383.3 yl}quinolin-2(1H)-one 94 4-amino-3-[5-(piperidin-3-ylamino)-1H-benzimidazol-2- 375.2 yl]quinolin-2(1H)-one 95 4-amino-5-fluoro-3-{5-[(pyridin-2-ylmethyl)amino]-1H- 401.3 benzimidazol-2-yl}quinolin-2(1H)-one 96 ethyl 4-{[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)- 465.5 1H-benzimidazol-5-yl]amino}piperidine-1-carboxylate 97 4-amino-5-fluoro-3-[5-(piperidin-3-ylamino)-1H-benzimidazol-2- 393.3 yl]quinolin-2(1H)-one 98 4-amino-3-(1H-benzimidazol-2-yl)-6-bromoquinolin-2(1H)-one 357.1 99 4-amino-3-(1H-benzimidazol-2-yl)-7-bromoquinolin-2(1H)-one 357.1 100 4-amino-3-(5-bromo-1H-benzimidazol-2-yl)quinolin-2(1H)-one 357.1 101 N,N-dimethyl-2-(2-oxo-1,2-dihydroquinolin-3-yl)-1H- 333.1 benzimidazole-5-carboxamide 102 4-amino-3-(5-thien-2-yl-1H-benzimidazol-2-yl)quinolin-2(1H)- 359.2 one 103 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N,N-dimethyl-1H- 384.1 benzimidazole-5-sulfonamide 104 4-amino-6-iodo-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 501.1 yl]quinolin-2(1H)-one 105 4-amino-3-(5-{2-[(dimethylamino)methyl]-morpholin-4-yl}-1H- 419.2 benzimidazol-2-yl)quinolin-2(1H)-one 106 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 547 yl)-7-chloro-6-iodoquinolin-2(1H)-one 107 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 431 yl)-6-nitroquinolin-2(1H)-one 108 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 401 yl)-6-methylquinolin-2(1H)-one 109 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 422 yl)-6,7-difluoroquinolin-2(1H)-one 110 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 421 yl)-7-chloroquinolin-2(1H)-one 111 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 465 yl)-6-bromoquinolin-2(1H)-one 112 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 411 yl)-2-oxo-1,2-dihydroquinoline-6-carbonitrile 113 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 404 yl)-6-fluoroquinolin-2(1H)-one 114 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 447 yl)-6,7-bis(methyloxy)quinolin-2(1H)-one 115 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 455 yl)-6,7-dichloroquinolin-2(1H)-one 116 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 531 2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4- carboxamide 117 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 478 yl)-6-fluoro-7-[(3-hydroxypropyl)amino]quinolin-2(1H)-one 118 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 448 yl)-7-(dimethylamino)-6-fluoroquinolin-2(1H)-one 119 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 404 yl)-5-fluoroquinolin-2(1H)-one 120 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 508 yl)-6-(4-nitrophenyl)quinolin-2(1H)-one 121 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 491 yl)-7-{[2-(dimethylamino)ethyl]amino}-6-fluoroquinolin-2(1H)- one 122 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 471 yl)-6-fluoro-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 123 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 493 yl)-6-[4-(methyloxy)phenyl]quinolin-2(1H)-one 124 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 490 yl)-6-fluoro-7-morpholin-4-ylquinolin-2(1H)-one 125 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6,7-difluoro-3-(3H- 423 imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one 126 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 508 yl)-6-(3-nitrophenyl)quinolin-2(1H)-one 127 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 531 2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-3- carboxamide 128 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 401 yl)-5-methylquinolin-2(1H)-one 129 6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 506 (3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one 130 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 421 yl)-5-chloroquinolin-2(1H)-one 131 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-fluoro-3-(3H- 491 imidazo[4,5-b]pyridin-2-yl)-7-morpholin-4-ylquinolin-2(1H)-one 132 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 460 yl)-7-(cyclopropylamino)-6-fluoroquinolin-2(1H)-one 133 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(3H- 521 imidazo[4,5-b]pyridin-2-yl)-2-oxo-1,2-dihydroquinolin-6- yl]phenyl}acetamide 134 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 503 yl)-6-fluoro-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one 135 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-fluoro-7-(1H- 472 imidazol-1-yl)-3-(3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)- one 136 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 525 yl)-6-fluoro-7-[(2-pyridin-2-ylethyl)amino]quinolin-2(1H)-one 137 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 488 yl)-6-fluoro-7-piperidin-1-ylquinolin-2(1H)-one 138 6-chloro-3-(3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one 298 139 ethyl 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 560 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxylate 140 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 519 yl)-6-(1-benzothien-2-yl)quinolin-2(1H)-one 141 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 474 yl)-6-fluoro-7-pyrrolidin-1-ylquinolin-2(1H)-one 142 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(3H-imidazo[4,5- 532 b]pyridin-2-yl)-6-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one 143 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(3H-imidazo[4,5- 494 b]pyridin-2-yl)-6-[2-(methyloxy)phenyl]quinolin-2(1H)-one 144 ethyl 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 560 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-3-carboxylate 145 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 491 yl)-6-(4-ethylphenyl)quinolin-2(1H)-one 146 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 476 yl)-6-fluoro-7-[(2-methylpropyl)amino]quinolin-2(1H)-one 147 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 401 yl)-5-methylquinolin-2(1H)-one 148 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-(2,4-dichlorophenyl)- 532 3-(3H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one 149 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 531 yl)-6-[3-(trifluoromethyl)phenyl]quinolin-2(1H)-one 150 3-(1H-benzimidazol-2-yl)-4-(dimethylamino)quinoline-2(1H)-one 305 151 4-hydroxy-3-(1H-imidazo[4,5-f]quinolin-2-yl)quinolin-2(1H)-one 329 152 4-hydroxy-3-(1H-imidazo[4,5-b]pyridin-2-yl)quinolin-2(1H)-one 279 153 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 525 benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 154 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 524 benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzamide 155 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 538 benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]phenyl}acetamide 156 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 525 benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 157 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 525 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 158 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H 538 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]phenyl}acetamide 159 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 511 yl)-7-chloro-6-(2-methylphenyl)quinolin-2(1H)-one 160 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 411 yl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile 161 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 417 yl)-7-(methyloxy)quinolin-2(1H)-one 162 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 506 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzamide 163 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 434 yl)-6-fluoro-7-(methyloxy)quinolin-2(1H)-one 164 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 464 yl)-6-chloro-7-(dimethylamino)quinolin-2(1H)-one 165 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 555 yl)-7-(dimethylamino)-6-iodoquinolin-2(1H)-one 166 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 573 benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 167 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 590 benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin-6- yl]benzoic acid 168 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 571 yl)-7-(methyloxy)-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)- one 169 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 401 yl)-8-methylquinolin-2(1H)-one 170 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 422 yl)-6,7-difluoroquinolin-2(1H)-one 171 3-(1H-benzimidazol-2-yl)-6-methyl-4-(piperidin-3- 374 ylamino)quinolin-2(1H)-one 172 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 493 yl)-6-[2-(methyloxy)phenyl]quinolin-2(1H)-one 173 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 493 yl)-6-[3-(methyloxy)phenyl]quinolin-2(1H)-one 174 3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-(piperidin-4- 396 ylamino)quinolin-2(1H)-one 175 3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-(pyrrolidin-3- 382 ylamino)quinolin-2(1H)-one 176 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(3-morpholin-4- 439 ylpropyl)amino]quinolin-2(1H)-one 177 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(piperidin- 480 4-ylamino)quinolin-2(1H)-one 178 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 494 [(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one 179 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5- 506 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 180 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(piperidin- 480 3-ylamino)quinolin-2(1H)-one 181 6-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-(5-morpholin-4- 468 yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 182 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5- 506 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 183 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 494 [(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one 184 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 494 [(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one 185 4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(5-morpholin- 494 4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 186 4-[(4-aminocyclohexyl)amino]-6-chloro-3-(5-morpholin-4-yl-1H- 494 benzimidazol-2-yl)quinolin-2(1H)-one 187 4-{[(2S)-2-amino-3-methylbutyl]amino}-6-chloro-3-(5-morpholin- 482 4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 188 4-({[4-(aminomethyl)phenyl]methyl}amino)-6-chloro-3-(5- 516 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 189 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 480 [(pyrrolidin-2-ylmethyl)amino]quinolin-2(1H)-one 190 4-{[(1R)-1-(aminomethyl)propyl]amino}-6-chloro-3-(5- 468 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 191 4-{[(1S)-2-amino-1-(phenylmethyl)ethyl]amino}-6-chloro-3-(5- 530 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 192 6-chloro-4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-(5- 537 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 193 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[1- 570 (phenylmethyl)piperidin-4-yl]amino}quinolin-2(1H)-one 194 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3- 524 morpholin-4-ylpropyl)amino]quinolin-2(1H)-one 195 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2- 508 piperidin-1-ylethyl)amino]quinolin-2(1H)-one 196 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(pyridin- 488 3-ylmethyl)amino]quinolin-2(1H)-one 197 6-chloro-4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-(5-morpholin- 505 4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 198 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(pyridin- 488 4-ylmethyl)amino]quinolin-2(1H)-one 199 6-chloro-4-{[2-(methylamino)ethyl]amino}-3-(5-morpholin-4-yl- 454 1H-benzimidazol-2-yl)quinolin-2(1H)-one 200 6-chloro-4-{[(2-methyl-1-piperidin-4-yl-1H-benzimidazol-5- 624 yl)methyl]amino}-3-(5-morpholin-4-yl-1H-benzimidazol-2- yl)quinolin-2(1H)-one 201 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2- 494 pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-one 202 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 466 (pyrrolidin-3-ylamino)quinolin-2(1H)-one 203 4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-[5-(4- 507 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 204 4-[(4-aminocyclohexyl)amino]-6-chloro-3-[5-(4-methylpiperazin- 507 1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 205 4-({[4-(aminomethyl)phenyl]methyl}amino)-6-chloro-3-[5-(4- 529 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 206 6-chloro-4-{[2-(methylamino)ethyl]amino}-3-[5-(4- 467 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 207 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 550 {[3-(4-methylpiperazin-1-yl)propyl]amino}quinolin-2(1H)-one 208 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 583 {[1-(phenylmethyl)piperidin-4-yl]amino}quinolin-2(1H)-one 209 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 507 [(2-pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-one 210 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 479 (pyrrolidin-3-ylamino)quinolin-2(1H)-one 211 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 493 (piperidin-4-ylamino)quinolin-2(1H)-one 212 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2- 508 piperidin-2-ylethyl)amino]quinolin-2(1H)-one 213 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-chloro-3-(5- 506 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 214 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(piperidin- 480 3-ylamino)quinolin-2(1H)-one 215 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 507 [(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one 216 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 493 {[(2S)-pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one 217 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4- 493 {[(2R)-pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one 218 6-chloro-4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-[5-(4- 521 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 219 6-chloro-4-({[(2R)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-[5-(4- 521 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 220 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2- 493 yl)-6-[4-(methyloxy)phenyl]quinolin-2(1H)-one 221 6-(3-aminophenyl)-4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 478 (1H-benzimidazol-2-yl)quinolin-2(1H)-one

TABLE of Additional Exemplary Compounds LC/MS m/z Example Name (MH⁺) 222 4-amino-3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one 277.3 223 4-amino-3-(1H-benzimidazol-2-yl)-6,7-dimethoxyquinolin- 337.3 2(1H)-one 224 3-(1H-benzimidazol-2-yl)-4-(dimethylamino)-1-methylquinolin- 319.4 2(1H)-one 225 3-(1H-benzimidazol-2-yl)-4-{[2-(dimethylamino)ethyl]amino}- 362.4 1-methylquinolin-2(1H)-one 226 4-amino-3-(1H-benzimidazol-2-yl)-1-methylquinolin-2(1H)-one 291.3 227 4-amino-3-(6-methyl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 291.3 228 3-(1H-benzimidazol-2-yl)-4-{[3-(1H-imidazol-1- 385.4 yl)propyl]amino}quinolin-2(1H)-one 229 3-(1H-benzimidazol-2-yl)-4-[(pyridin-3- 368.4 ylmethyl)amino]quinolin-2(1H)-one 230 4-amino-3-(1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one 295.3 231 3-(1H-benzimidazol-2-yl)-4-pyrrolidin-1-ylquinolin-2(1H)-one 331.4 232 3-(1H-benzimidazol-2-yl)-4-[(pyridin-4- 368.4 ylmethyl)amino]quinolin-2(1H)-one 233 3-(1H-benzimidazol-2-yl)-4-{[2-(1-methylpyrrolidin-2- 388.5 yl)ethyl]amino}quinolin-2(1H)-one 234 4-amino-3-(1H-benzimidazol-2-yl)-7-methylquinolin-2(1H)-one 291.3 235 4-amino-3-(1H-benzimidazol-2-yl)-7-chloroquinolin-2(1H)-one 311.7 236 4-amino-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one 311.7 237 4-amino-3-[6-(3-aminopyrrolidin-1-yl)-1H-benzimidazol-2- 361.4 yl]quinolin-2(1H)-one 238 3-(1H-benzimidazol-2-yl)-4-(diethylamino)quinolin-2(1H)-one 333.4 239 3-(1H-benzimidazol-2-yl)-4-(1,2-dimethylhydrazino)quinolin- 320.4 2(1H)-one 240 4-amino-3-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]quinolin- 345.3 2(1H)-one 241 4-amino-3-(5,6-dichloro-1H-benzimidazol-2-yl)quinolin-2(1H)- 346.2 one 242 4-(3-aminopyrrolidin-1-yl)-3-(5-morpholin-4-yl-1H- 431.5 benzimidazol-2-yl)quinolin-2(1H)-one 243 4-amino-5-fluoro-3-(5-methyl-1H-benzimidazol-2-yl)quinolin- 309.3 2(1H)-one 244 4-amino-3-(1H-benzimidazol-2-yl)-6-nitroquinolin-2(1H)-one 322.3 245 4-amino-3-(4-methyl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 291.3 246 4-amino-3-(6-ethoxy-1H-benzimidazol-2-yl)quinolin-2(1H)-one 321.4 247 4-amino-3-(7-hydroxy-1H-benzimidazol-2-yl)quinolin-2(1H)- 293.3 one 248 4-amino-3-(6-tert-butyl-1H-benzimidazol-2-yl)quinolin-2(1H)- 333.4 one 249 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzimidazole- 302.3 5-carbonitrile 250 4-amino-3-(5,6-dimethyl-1H-benzimidazol-2-yl)quinolin-2(1H)- 305.4 one 251 4-amino-3-(4,5-dimethyl-1H-benzimidazol-2-yl)quinolin-2(1H)- 305.4 one 252 4-amino-6-chloro-3-(5-methyl-1H-benzimidazol-2-yl)quinolin- 325.8 2(1H)-one 253 4-amino-3-(1H-benzimidazol-2-yl)-6,8-dichloroquinolin-2(1H)- 346.2 one 254 4-amino-3-(1H-benzimidazol-2-yl)-5-chloroquinolin-2(1H)-one 311.7 255 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N,N-dimethyl-1H- 348.4 benzimidazole-5-carboxamide 256 4-amino-3-{5-[3-(dimethylamino)pyrrolidin-1-yl]-1H- 389.5 benzimidazol-2-yl}quinolin-2(1H)-one 257 4-amino-3-(6-methoxy-5-methyl-1H-benzimidazol-2-yl)quinolin- 321.4 2(1H)-one 258 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H-benzimidazole- 319.3 6-carboximidamide 259 4-amino-7-(3-aminophenyl)-3-(1H-benzimidazol-2-yl)quinolin- 368.4 2(1H)-one 260 4-amino-3-(1H-benzimidazol-2-yl)-7-thien-2-ylquinolin-2(1H)- 359.4 one 261 4-amino-3-(5-thien-3-yl-1H-benzimidazol-2-yl)quinolin-2(1H)- 359.4 one 262 4-amino-3-(1H-benzimidazol-2-yl)-7-thien-3-ylquinolin-2(1H)- 359.4 one 263 4-{[(1S,2R)-2-aminocyclohexyl]amino}-3-(5-morpholin-4-yl- 459.6 1H-benzimidazol-2-yl)quinolin-2(1H)-one 264 4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(5-morpholin-4-yl- 459.6 1H-benzimidazol-2-yl)quinolin-2(1H)-one 265 4-{[(1S,2S)-2-aminocyclohexyl]amino}-3-(5-morpholin-4-yl-1H- 459.6 benzimidazol-2-yl)quinolin-2(1H)-one 266 4-amino-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H- 390.5 benzimidazol-2-yl}quinolin-2(1H)-one 267 3-(1H-benzimidazol-2-yl)-4-morpholin-4-ylquinolin-2(1H)-one- 347.4 268 3-(1H-benzimidazol-2-yl)-4-(piperidin-3-ylamino)quinolin- 360.4 2(1H)-one 269 4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(5-chloro-1H- 420.9 benzimidazol-2-yl)quinolin-2(1H)-one 270 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-methyl- 434.9 1H-benzimidazol-2-yl)quinolin-2(1H)-one 271 6-chloro-3-(5-methyl-1H-benzimidazol-2-yl)-4-(piperidin-3- 408.9 ylamino)quinolin-2(1H)-one 272 3-(1H-benzimidazol-2-yl)-4-[(2-hydroxyethyl)amino]quinolin- 321.4 2(1H)-one 273 3-(1H-benzimidazol-2-yl)-6-chloro-4-(piperidin-3- 394.9 ylamino)quinolin-2(1H)-one 274 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(1S)-1- 421.9 cyclohexylethyl]amino}quinolin-2(1H)-one 275 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(piperidin-3- 408.9 ylmethyl)amino]quinolin-2(1H)-one 276 3-(1H-benzimidazol-2-yl)-6-chloro-4-(pyridin-4- 388.8 ylamino)quinolin-2(1H)-one 277 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(piperidin-4- 408.9 ylethyl)amino]quinolin-2(1H)-one 278 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-morpholin-4- 424.9 ylethyl)amino]quinolin-2(1H)-one 279 3-(1H-benzimidazol-2-yl)-6-chloro-4- 393.9 (cyclohexylamino)quinolin-2(1H)-one 280 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[3-(1H-imidazol-1- 419.9 yl)propyl]amino}quinolin-2(1H)-one 281 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[2- 382.9 (dimethylamino)ethyl]amino}quinolin-2(1H)-one 282 3-(1H-benzimidazol-2-yl)-6-chloro-4- 407.9 [(cyclohexylmethyl)amino]quinolin-2(1H)-one 283 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(tetrahydrofuran-2- 395.9 ylmethyl)amino]quinolin-2(1H)-one 284 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(pyridin-4- 402.9 ylmethyl)amino]quinolin-2(1H)-one 285 3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-(piperidin-3- 396.4 ylamino)quinolin-2(1H)-one 286 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 465.4 2-yl)-6-bromoquinolin-2(1H)-one 287 3-(1H-benzimidazol-2-yl)-6-fluoro-4-(piperidin-3- 378.4 ylamino)quinolin-2(1H)-one 288 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 400.5 2-yl)-6-methylquinolin-2(1H)-one 289 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 404.5 2-yl)-6-fluoroquinolin-2(1H)-one 290 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1- 417.5 propylquinolin-2(1H)-one 291 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(1-ethylpyrrolidin-2- 422.9 yl)methyl]amino}quinolin-2(1H)-one 292 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[3-(2-oxopyrrolidin-1- 436.9 yl)propyl]amino}quinolin-2(1H)-one 293 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(piperidin-2- 408.9 ylmethyl)amino]quinolin-2(1H)-one 294 3-(1H-benzimidazol-2-yl)-6-chloro-4-(4-methyl-1,4-diazepan-1- 408.9 yl)quinolin-2(1H)-one 295 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(pyridin-3- 402.9 ylmethyl)amino]quinolin-2(1H)-one 296 4-anilino-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one 387.8 297 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(5-methylpyrazin-2- 417.9 yl)methyl]amino}quinolin-2(1H)-one 298 3-(1H-benzimidazol-2-yl)-6-chloro-4-(piperidin-4- 402.9 ylamino)quinolin-2(1H)-one 299 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[2-(1-methylpyrrolidin-2- 422.9 yl)ethyl]amino}quinolin-2(1H)-one 300 3-(1H-benzimidazol-2-yl)-4-[(1H-benzimidazol-5- 441.9 ylmethyl)amino]-6-chloroquinolin-2(1H)-one 301 3-(1H-benzimidazol-2-yl)-6-chloro-4-(piperidin-4- 394.9 ylamino)quinolin-2(1H)-one 302 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(4- 409.9 hydroxycyclohexyl)amino]quinolin-2(1H)-one 303 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 404.5 2-yl)-5-fluoroquinolin-2(1H)-one 304 3-(1H-benzimidazol-2-yl)-6,8-dimethyl-4-(piperidin-3- 388.5 ylamino)quinolin-2(1H)-one 305 3-(1H-benzimidazol-2-yl)-5-fluoro-4-(piperidin-3- 378.4 ylamino)quinolin-2(1H)-one 306 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 414.5 2-yl)-6,8-dimethylquinolin-2(1H)-one 307 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 414.5 2-yl)-6,8-dimethylquinolin-2(1H)-one 308 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 420.9 2-yl)-7-chloroquinolin-2(1H)-one 309 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-piperidin-1- 422.9 ylethyl)amino]quinolin-2(1H)-one 310 4-({2-[(4-amino-5-nitropyridin-2-yl)amino]ethyl}amino)-3-(1H- 491.9 benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one 311 3-(1H-benzimidazol-2-yl)-6-chloro-4-({2-[(5-nitropyridin-2- 476.9 yl)amino]ethyl}amino)quinolin-2(1H)-one 312 3-(1H-benzimidazol-2-yl)-4-[(1H-benzimidazol-2- 441.9 ylmethyl)amino]-6-chloroquinolin-2(1H)-one 313 3-(1H-benzimidazol-2-yl)-6-chloro-4-(2,5- 392.9 diazabicyclo[2.2.1]hept-2-yl)quinolin-2(1H)-one 314 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-{[5- 499.9 (trifluoromethyl)pyridin-2-yl]amino}ethyl)amino]quinolin- 2(1H)-one 315 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 400.5 2-yl)-7-methylquinolin-2(1H)-one 316 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 400.5 2-yl)-7-methylquinolin-2(1H)-one 317 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[(2R)-pyrrolidin-2- 394.9 ylmethyl]amino}quinolin-2(1H)-one 318 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(pyrrolidin-2- 394.9 ylmethyl)amino]quinolin-2(1H)-one 319 6-[(2-{[3-(1H-benzimidazol-2-yl)-6-chloro-2-oxo-1,2- 474.9 dihydroquinolin-4-yl]amino}ethyl)amino]nicotinamide 320 3-(1H-benzimidazol-2-yl)-6-chloro-4-(pyrrolidin-3- 380.8 ylamino)quinolin-2(1H)-one 321 4-{[(2R)-2-aminobutyl]amino}-3-(1H-benzimidazol-2-yl)-6- 382.9 chloroquinolin-2(1H)-one 322 4-{[(2S)-2-amino-3-phenylpropyl]amino}-3-(1H-benzimidazol- 444.9 2-yl)-6-chloroquinolin-2(1H)-one 323 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-6- 408.9 chloroquinolin-2(1H)-one 324 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 512.4 2-yl)-6-iodoquinolin-2(1H)-one 325 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 512.4 2-yl)-6-iodoquinolin-2(1H)-one 326 3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-(piperidin-3- 420.5 ylamino)quinolin-2(1H)-one 327 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 446.5 2-yl)-6,7-dimethoxyquinolin-2(1H)-one 328 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 431.5 2-yl)-6-nitroquinolin-2(1H)-one 329 3-(1H-benzimidazol-2-yl)-6-iodo-4-(piperidin-3- 486.3 ylamino)quinolin-2(1H)-one 330 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 420.9 2-yl)-5-chloroquinolin-2(1H)-one 331 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(1-piperidin-4-yl-1H- 525.0 benzimidazol-6-yl)methyl]amino}quinolin-2(1H)-one 332 3-(1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-3- 388.5 ylmethyl)amino]quinolin-2(1H)-one 333 3-(1H-benzimidazol-2-yl)-6-methyl-4-(piperidin-4- 374.5 ylamino)quinolin-2(1H)-one 334 3-(1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-4- 388.5 ylmethyl)amino]quinolin-2(1H)-one 335 3-(1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-2- 388.5 ylmethyl)amino]quinolin-2(1H)-one 336 4-{[4-(2-aminoethoxy)benzyl]amino}-3-(1H-benzimidazol-2-yl)- 460.9 6-chloroquinolin-2(1H)-one 337 4-{[2-(2-aminoethoxy)benzyl]amino}-3-(1H-benzimidazol-2-yl)- 460.9 6-chloroquinolin-2(1H)-one 338 4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(5-hydroxy-1H- 402.5 benzimidazol-2-yl)quinolin-2(1H)-one 339 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 411.5 2-yl)-2-oxo-1,2-dihydroquinoline-6-carbonitrile 340 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 418.5 2-yl)-6,7-dihydroxyquinolin-2(1H)-one 341 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 418.5 2-yl)-6,7-dihydroxyquinolin-2(1H)-one 342 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 430.5 2-yl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid 343 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 404.5 2-yl)-7-fluoroquinolin-2(1H)-one 344 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 404.5 2-yl)-7-fluoroquinolin-2(1H)-one 345 2-(4-amino-2-oxo-1-propyl-1,2-dihydroquinolin-3-yl)-1H- 344.4 benzimidazole-6-carbonitrile 346 tert-butyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 567.7 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-3,6- dihydropyridine-1(2H)-carboxylate 347 tert-butyl 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 567.7 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-3,6- dihydropyridine-1(2H)-carboxylate 348 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 467.6 2-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one 349 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 468.6 2-yl)-6-thien-2-ylquinolin-2(1H)-one 350 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 467.6 2-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one 351 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 498.5 2-yl)-6-(2,4-difluorophenyl)quinolin-2(1H)-one 352 tert-butyl 2-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 551.7 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-1H-pyrrole- 1-carboxylate 353 tert-butyl 2-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 551.7 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]-1H-pyrrole- 1-carboxylate 354 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 463.6 2-yl)-6-pyridin-2-ylquinolin-2(1H)-one 355 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 468.6 2-yl)-6-thien-2-ylquinolin-2(1H)-one 356 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 498.5 2-yl)-6-(2,4-difluorophenyl)quinolin-2(1H)-one 357 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 468.6 2-yl)-6-thien-3-ylquinolin-2(1H)-one 358 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 487.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzonitrile 359 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 497.0 2-yl)-6-(2-chlorophenyl)quinolin-2(1H)-one 360 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.6 2-yl)-6-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one 361 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 492.6 2-yl)-6-(3-methoxyphenyl)quinolin-2(1H)-one 362 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 463.6 2-yl)-6-pyridin-3-ylquinolin-2(1H)-one 363 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 463.6 2-yl)-6-pyridin-4-ylquinolin-2(1H)-one 364 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 430.5 2-yl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid 365 3-(5-hydroxy-1H-benzimidazol-2-yl)-4-(piperidin-3- 376.4 ylamino)quinolin-2(1H)-one 366 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 400.5 2-yl)-8-methylquinolin-2(1H)-one 367 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 497.0 2-yl)-6-(2-chlorophenyl)quinolin-2(1H)-one 368 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.6 2-yl)-6-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one 369 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 487.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzonitrile 370 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 468.6 2-yl)-6-thien-3-ylquinolin-2(1H)-one 371 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 463.6 2-yl)-6-pyridin-4-ylquinolin-2(1H)-one 372 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 492.6 2-yl)-6-(2-methoxyphenyl)quinolin-2(1H)-one 373 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 476.6 2-yl)-6-(2-methylphenyl)quinolin-2(1H)-one 374 6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 504.6 (1H-benzimidazol-2-yl)quinolin-2(1H)-one 375 6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 504.6 (1H-benzimidazol-2-yl)quinolin-2(1H)-one 376 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 506.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoic acid 377 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 519.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6- yl]phenyl}acetamide 378 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 498.5 2-yl)-6-(2,6-difluorophenyl)quinolin-2(1H)-one 379 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 506.6 2-yl)-6-(1,3-benzodioxol-5-yl)quinolin-2(1H)-one 380 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 497.0 2-yl)-6-(4-chlorophenyl)quinolin-2(1H)-one 381 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 490.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6- yl]benzaldehyde 382 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 508.7 2-yl)-6-[4-(methylthio)phenyl]quinolin-2(1H)-one 383 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 505.6 2-yl)-6-[4-(dimethylamino)phenyl]quinolin-2(1H)-one 384 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 515.0 2-yl)-6-(4-chloro-2-fluorophenyl)quinolin-2(1H)-one 385 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 531.5 2-yl)-6-(2,4-dichlorophenyl)quinolin-2(1H)-one 386 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 462.6 2-yl)-6-phenylquinolin-2(1H)-one 387 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(1-ethylpiperidin-3- 422.9 yl)amino]quinolin-2(1H)-one 388 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 530.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxamide 389 ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 559.7 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxylate 390 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 530.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-3-carboxamide 391 ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 559.7 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-3-carboxylate 392 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 470.5 2-yl)-6-fluoro-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 393 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 490.6 2-yl)-7-{[2-(dimethylamino)ethyl]amino}-6-fluoroquinolin- 2(1H)-one 394 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 489.6 2-yl)-6-fluoro-7-morpholin-4-ylquinolin-2(1H)-one 395 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 447.5 2-yl)-7-(dimethylamino)-6-fluoroquinolin-2(1H)-one 396 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 465.4 2-yl)-7-bromoquinolin-2(1H)-one 397 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 531.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxylic acid 398 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 531.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-3-carboxylic acid 399 methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 520.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoate 400 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 505.6 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzamide 401 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 540.7 2-yl)-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one 402 methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 535.6 (1H-benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 403 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 541.0 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 404 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 554.1 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]phenyl}acetamide 405 6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 539.0 (1H-benzimidazol-2-yl)-7-chloroquinolin-2(1H)-one 406 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 527.0 2-yl)-7-chloro-6-(2-methoxyphenyl)quinolin-2(1H)-one 407 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 565.9 2-yl)-7-chloro-6-(2,4-dichlorophenyl)quinolin-2(1H)-one 408 6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 539.0 (1H-benzimidazol-2-yl)-7-chloroquinolin-2(1H)-one 409 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 540.0 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzamide 410 methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 555.0 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 411 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 504.6 2-yl)-7-[[2-(dimethylamino)ethyl](methyl)amino]-6- fluoroquinolin-2(1H)-one 412 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 491.6 2-yl)-6-fluoro-7-[(3-methoxypropyl)amino]quinolin-2(1H)-one 413 N-{(3R)-1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 530.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]pyrrolidin-3-yl}acetamide 414 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 544.6 2-yl)-6-fluoro-7-{[3-(2-oxopyrrolidin-1- yl)propyl]amino}quinolin-2(1H)-one 415 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-azepan-1-yl-3-(1H- 501.6 benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one 416 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 469.5 2-yl)-6-fluoro-7-(1H-pyrrol-1-yl)quinolin-2(1H)-one 417 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 484.5 2-yl)-6-fluoro-7-(2-methyl-1H-imidazol-1-yl)quinolin-2(1H)-one 418 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 473.6 2-yl)-6-fluoro-7-pyrrolidin-1-ylquinolin-2(1H)-one 419 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 487.6 2-yl)-6-fluoro-7-piperidin-1-ylquinolin-2(1H)-one 420 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 502.6 2-yl)-6-fluoro-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one 421 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 477.6 2-yl)-6-fluoro-7-[(3-hydroxypropyl)amino]quinolin-2(1H)-one 422 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 506.0 2-yl)-6-chloro-7-morpholin-4-ylquinolin-2(1H)-one 423 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 519.1 2-yl)-6-chloro-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one 424 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 504.0 2-yl)-6-chloro-7-piperidin-1-ylquinolin-2(1H)-one 425 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 506.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid 426 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 531.5 2-yl)-7-(2,4-dichlorophenyl)quinolin-2(1H)-one 427 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 429.5 2-yl)-7-(dimethylamino)quinolin-2(1H)-one 428 7-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 504.6 (1H-benzimidazol-2-yl)quinolin-2(1H)-one 429 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 476.6 2-yl)-7-(2-methylphenyl)quinolin-2(1H)-one 430 7-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 504.6 (1H-benzimidazol-2-yl)quinolin-2(1H)-one 431 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 492.6 2-yl)-7-(2-methoxyphenyl)quinolin-2(1H)-one 432 3-(1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-2- 410.4 ylmethyl)amino]quinolin-2(1H)-one 433 N-[3-(1H-benzimidazol-2-yl)-6,7-difluoro-2-oxo-1,2- 371.3 dihydroquinolin-4-yl]glycine 434 N-[3-(1H-benzimidazol-2-yl)-6,7-difluoro-2-oxo-1,2- 385.3 dihydroquinolin-4-yl]-beta-alanine 435 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(6-fluoro-1H- 464.5 benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one 436 3-(6-fluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4-(piperidin- 438.5 3-ylamino)quinolin-2(1H)-one 437 3-(6-fluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4-(pyrrolidin- 424.4 3-ylamino)quinolin-2(1H)-one 438 4-[(4-aminocyclohexyl)amino]-3-(6-fluoro-1H-benzimidazol-2- 452.5 yl)-6,7-dimethoxyquinolin-2(1H)-one 439 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(6-fluoro-1H- 464.5 benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one 440 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 461.6 2-yl)-7-[ethyl(methyl)amino]-6-fluoroquinolin-2(1H)-one 441 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 475.6 2-yl)-7-(diethylamino)-6-fluoroquinolin-2(1H)-one 442 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 516.6 2-yl)-7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-6- fluoroquinolin-2(1H)-one 443 7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3- 511.6 ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one 444 ethyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 534.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoate 445 methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 520.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoate 446 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 518.6 2-yl)-7-{[2-(diethylamino)ethyl]amino}-6-fluoroquinolin-2(1H)- one 447 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 516.6 2-yl)-6-fluoro-7-[(2-pyrrolidin-1-ylethyl)amino]quinolin-2(1H)- one 448 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.7 2-yl)-6-fluoro-7-[(2-piperidin-1-ylethyl)amino]quinolin-2(1H)- one 449 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 504.6 2-yl)-7-{[3-(dimethylamino)propyl]amino}-6-fluoroquinolin- 2(1H)-one 450 N-(2-{[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 504.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]amino}ethyl)acetamide 451 N-{1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 584.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide 452 3-{[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 472.5 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]amino}propanenitrile 453 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 463.5 2-yl)-6-fluoro-7-[(2-hydroxyethyl)amino]quinolin-2(1H)-one 454 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 477.6 2-yl)-6-fluoro-7-[(2-methoxyethyl)amino]quinolin-2(1H)-one 455 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 503.6 2-yl)-6-fluoro-7-(3-hydroxypiperidin-1-yl)quinolin-2(1H)-one 456 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 504.6 2-yl)-7-[[2-(dimethylamino)ethyl](methyl)amino]-6- fluoroquinolin-2(1H)-one 457 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 504.6 2-yl)-7-{[3-(dimethylamino)propyl]amino}-6-fluoroquinolin- 2(1H)-one 458 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 518.6 2-yl)-7-{[2-(diethylamino)ethyl]amino}-6-fluoroquinolin-2(1H)- one 459 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 516.6 2-yl)-6-fluoro-7-[(2-pyrrolidin-1-ylethyl)amino]quinolin-2(1H)- one 460 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.7 2-yl)-6-fluoro-7-(3-hydroxypiperidin-1-yl)quinolin-2(1H)-one 461 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 544.6 2-yl)-6-fluoro-7-{[3-(2-oxopyrrolidin-1- yl)propyl]amino}quinolin-2(1H)-one 462 N-(2-{[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 504.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]amino}ethyl)acetamide 463 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 491.6 2-yl)-6-fluoro-7-[(3-methoxypropyl)amino]quinolin-2(1H)-one 464 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 477.6 2-yl)-6-fluoro-7-[(2-methoxyethyl)amino]quinolin-2(1H)-one 465 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 463.5 2-yl)-6-fluoro-7-[(2-hydroxyethyl)amino]quinolin-2(1H)-one 466 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 461.6 2-yl)-7-[ethyl(methyl)amino]-6-fluoroquinolin-2(1H)-one 467 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 475.6 2-yl)-7-(diethylamino)-6-fluoroquinolin-2(1H)-one 468 N-{(3R)-1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 530.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]pyrrolidin-3-yl}acetamide 469 N-{(3S)-1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 530.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]pyrrolidin-3-yl}acetamide 470 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 516.6 2-yl)-7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-6- fluoroquinolin-2(1H)-one 471 N-{1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 584.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide 472 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-azepan-1-yl-3-(1H- 501.6 benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one 473 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 503.6 2-yl)-6-fluoro-7-(3-hydroxypiperidin-1-yl)quinolin-2(1H)-one 474 3-{[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 472.5 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]amino}propanenitrile 475 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 469.5 2-yl)-6-fluoro-7-(1H-pyrrol-1-yl)quinolin-2(1H)-one 476 7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3S)-1-azabicyclo[2.2.2]oct-3- 511.6 ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one 477 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 484.5 2-yl)-6-fluoro-7-(2-methyl-1H-imidazol-1-yl)quinolin-2(1H)-one 478 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 516.6 2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6- fluoroquinolin-2(1H)-one 479 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 434.5 2-yl)-6-fluoro-7-methoxyquinolin-2(1H)-one 480 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 516.6 2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6- fluoroquinolin-2(1H)-one 481 N-{(3S)-1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 530.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]pyrrolidin-3-yl}acetamide 482 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 524.6 2-yl)-6-fluoro-7-[(2-pyridin-2-ylethyl)amino]quinolin-2(1H)-one 483 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 475.6 2-yl)-6-fluoro-7-(isobutylamino)quinolin-2(1H)-one 484 methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 570.1 (1H-benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 485 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 575.1 2-yl)-7-chloro-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one 486 methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 555.0 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 487 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 531.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxylic acid 488 1-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 531.6 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-3-carboxylic acid 489 4-[(4-aminobenzyl)amino]-3-(1H-benzimidazol-2-yl)-6,7- 442.5 dimethoxyquinolin-2(1H)-one 490 4-(2-{[3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-2-oxo-1,2- 520.6 dihydroquinolin-4-yl]amino}ethyl)benzenesulfonamide 491 4-[(3-aminopropyl)amino]-3-(1H-benzimidazol-2-yl)-6,7- 394.4 dimethoxyquinolin-2(1H)-one 492 4-[(2-aminoethyl)amino]-3-(1H-benzimidazol-2-yl)-6,7- 380.4 dimethoxyquinolin-2(1H)-one 493 3-(1H-benzimidazol-2-yl)-4-{[2-(1H-imidazol-5- 431.5 yl)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one 494 3-(1H-benzimidazol-2-yl)-4-{[2-(1H-benzimidazol-2- 481.5 yl)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one 495 4-{[(4-amino-2-methylpyrimidin-5-yl)methyl]amino}-3-(1H- 458.5 benzimidazol-2-yl)-6,7-dimethoxyquinoln-2(1H)-one 496 3-(1H-benzimidazol-2-yl)-4-{[2-(5-fluoro-1H-indol-3- 498.5 yl)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one 497 4-{[2-(4-aminophenyl)ethyl]amino}-3-(1H-benzimidazol-2-yl)- 456.5 6,7-dimethoxyquinolin-2(1H)-one 498 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 471.6 2yl)-7-morpholin-4-ylquinolin-2(1H)-one 499 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5,6-difluoro-1H- 430.5 benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one 500 methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 535.6 (1H-benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7- yl]benzoate 501 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 540.7 2-yl)-7-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one 502 methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 520.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoate 503 methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 520.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoate 504 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 519.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7- yl]phenyl}acetamide 505 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5,6-difluoro-1H- 482.5 benzimidazol-2-yl)-6,7-dimethoxyquinolin-2(1H)-one 506 3-(5,6-difluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4- 456.5 (piperidin-3-ylamino)quinolin-2(1H)-one 507 4-[(4-aminocyclohexyl)amino]-3-(5,6-difluoro-1H-benzimidazol- 470.5 2-yl)-6,7-dimethoxyquinolin-2(1H)-one 508 3-(5,6-difluoro-1H-benzimidazol-2-yl)-6,7-dimethoxy-4- 442.4 (pyrrolidin-3-ylamino)quinolin-2(1H)-one 509 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 487.0 2-yl)-6-chloro-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 510 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 459.6 2-yl)-7-[(3-hydroxypropyl)amino]quinolin-2(1H)-one 511 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 526.7 2-yl)-7-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}quinolin-2(1H)- one 512 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 484.6 2-yl)-7-(4-methylpiperazin-1-yl)quinolin-2(1H)-one 513 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 487.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzonitrile 514 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.6 2-yl)-7-[2-(trifluoromethyl)phenyl]quinolin-2(1H)-one 515 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 506.6 2-yl)-7-(1,3-benzodioxol-5-yl)quinolin-2(1H)-one 516 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 499.6 2-yl)-7-(morpholin-4-ylcarbonyl)quinolin-2(1H)-one 517 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 457.5 2-yl)-N,N-dimethyl-2-oxo-1,2-dihydroquinoline-7-carboxamide 518 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 429.5 2-yl)-2-oxo-1,2-dihydroquinoline-7-carboxamide 519 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 506.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid 520 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 465.4 2-yl)-7-bromoquinolin-2(1H)-one 521 4-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 661.8 benzimidazol-2-yl)-7-[4-(ethoxycarbonyl)piperidin-1-yl]-2-oxo- 1,2-dihydroquinolin-6-yl}benzoic acid 522 4-[7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3- 613.7 ylamino]-3-(1H-benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin- 6-yl]benzoic acid 523 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 549.6 benzimidazol-2-yl)-7-(dimethylamino)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 524 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 572.6 benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 525 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.4 2-yl)-7-fluoro-6-iodoquinolin-2(1H)-one 526 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 558.6 2-yl)-7-fluoro-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one 527 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 523.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzamide 528 6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 522.6 (1H-benzimidazol-2-yl)-7-fluoroquinolin-2(1H)-one 529 methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 538.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 530 methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 553.6 (1H-benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 531 6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 522.6 (1H-benzimidazol-2-yl)-7-fluoroquinolin-2(1H)-one 532 methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 538.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 533 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 494.6 2-yl)-7-fluoro-6-(2-methylphenyl)quinolin-2(1H)-one 534 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 510.6 2-yl)-7-fluoro-6-(2-methoxyphenyl)quinolin-2(1H)-one 535 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 549.4 2-yl)-6-(2,4-dichlorophenyl)-7-fluoroquinolin-2(1H)-one 536 ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 667.6 benzimidazol-2-yl)-6-iodo-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxylate 537 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 578.4 2-yl)-7-(1H-imidazol-1-yl)-6-iodoquinolin-2(1H)-one 538 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 556.7 2-yl)-6-(2-ethylphenyl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 539 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 571.7 benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzamide 540 6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 570.7 (1H-benzimidazol-2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 541 6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 587.7 (1H-benzimidazol-2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 542 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 585.7 benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]phenyl}acetamide 543 6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 570.7 (1H-benzimidazol-2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 544 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 542.7 2-yl)-7-(1H-imidazol-1-yl)-6-(2-methylphenyl)quinolin-2(1H)- one 545 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 558.7 2-yl)-7-(1H-imidazol-1-yl)-6-(2-methoxyphenyl)quinolin-2(1H)- one 546 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 597.5 2-yl)-6-(2,4-dichlorophenyl)-7-(1H-imidazol-1-yl)quinolin- 2(1H)-one 547 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 490.6 2-yl)-6-(2-ethylphenyl)quinolin-2(1H)-one 548 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 508.6 2-yl)-6-(2-ethylphenyl)-7-fluoroquinolin-2(1H)-one 549 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 506.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-6-yl]benzoic acid 550 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 556.0 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 551 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 541.0 benzimidazol-2-yl)-7-chloro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 552 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 510.6 2-yl)-6-fluoro-7-[(pyridin-2-ylmethyl)amino]quinolin-2(1H)-one 553 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 527.6 2-yl)-6-fluoro-7-[(3-pyrrolidin-1-ylpropyl)amino]quinolin-2(1H)- one 554 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 510.6 2-yl)-6-fluoro-7-[(pyridin-3-ylmethyl)amino]quinolin-2(1H)-one 555 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.7 2-yl)-6-fluoro-7-[(3-pyrrolidin-1-ylpropyl)amino]quinolin-2(1H)- one 556 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 489.6 2-yl)-6-fluoro-7-[(3R)-3-hydroxypyrrolidin-1-yl]quinolin-2(1H)- one 557 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.7 2-yl)-6-fluoro-7-{[2-(1-methylpyrrolidin-2- yl)ethyl]amino}quinolin-2(1H)-one 558 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 510.6 2-yl)-6-fluoro-7-[(pyridin-4-ylmethyl)amino]quinolin-2(1H)-one 559 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 551.7 2-yl)-6-fluoro-7-[3-(methylsulfonyl)pyrrolidin-1-yl]quinolin- 2(1H)-one 560 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 550.7 2-yl)-6-fluoro-7-(3-pyridin-4-ylpyrrolidin-1-yl)quinolin-2(1H)- one 561 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 532.6 2-yl)-6-fluoro-7-[(2-morpholin-4-ylethyl)amino]quinolin-2(1H)- one 562 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 579.7 2-yl)-6-fluoro-7-[4-(pyridin-4-ylmethyl)piperazin-1-yl]quinolin- 2(1H)-one 563 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 509.6 2-yl)-7-(benzylamino)-6-fluoroquinolin-2(1H)-one 564 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 550.7 2-yl)-6-fluoro-7-(2-pyridin-3-ylpyrrolidin-1-yl)quinolin-2(1H)- one 565 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 524.6 2-yl)-6-fluoro-7-[(2-pyridin-4-ylethyl)amino]quinolin-2(1H)-one 566 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 546.7 2-yl)-6-fluoro-7-[(3-morpholin-4-ylpropyl)amino]quinolin- 2(1H)-one 567 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 524.6 2-yl)-6-fluoro-7-[(4-hydroxycyclohexyl)amino]quinolin-2(1H)- one 568 7-{[2-(4-aminophenyl)ethyl]amino}-4-[(3R)-1- 538.6 azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-6- fluoroquinolin-2(1H)-one 569 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 517.6 2-yl)-6-fluoro-7-[(4-hydroxycyclohexyl)amino]quinolin-2(1H)- one 570 4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)- 516.6 6-fluoro-7-[(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one 571 4-(1-azabicyclo[2.2.2]oct-3-ylamino)-3-(1H-benzimidazol-2-yl)- 488.6 6-fluoro-7-(pyrrolidin-3-ylamino)quinolin-2(1H)-one 572 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 586.7 benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 573 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 547.1 benzimidazol-2-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxamide 574 ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 576.1 benzimidazol-2-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxylate 575 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 452.5 2-yl)-7-(1H-imidazol-1-yl)quinolin-2(1H)-one 576 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 466.6 2-yl)-7-(2-methyl-1H-imidazol-1-yl)quinolin-2(1H)-one 577 ethyl 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 541.7 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4- carboxylate 578 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 512.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4- carboxamide 579 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 479.6 2-yl)-6-fluoro-7-[(2-mercaptoethyl)amino]quinolin-2(1H)-one 580 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 579.7 2-yl)-6-fluoro-7-[4-(pyridin-3-ylmethyl)piperazin-1-yl]quinolin- 2(1H)-one 581 3-(1H-benzimidazol-2-yl)-4-[(2-hydroxyethyl)amino]-6,7- 381.4 dimethoxyquinolin-2(1H)-one 582 3-(1H-benzimidazol-2-yl)-4-[(3-hydroxypropyl)amino]-6,7- 395.4 dimethoxyquinolin-2(1H)-one 583 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 531.6 2-yl)-6-fluoro-7-{[(1- hydroxycyclohexyl)methyl]amino}quinolin-2(1H)-one 584 3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-[(3-pyrrolidin-1- 448.5 ylpropyl)amino]quinolin-2(1H)-one 585 4[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 411.5 2-yl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile 586 3-(1H-benzimidazol-2-yl)-6-chloro-4-(pyridine-3- 388.8 ylamino)quinolin-2(1H)-one 587 3-(1H-benzimidazol-2-yl)-4-[(1-benzylpiperidin-4-yl)amino]-6- 485.0 chloroquinolin-2(1H)-one 588 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 416.5 2-yl)-7-methoxyquinolin-2(1H)-one 589 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 495.4 2-yl)-6-bromo-7-methoxyquinolin-2(1H)-one 590 3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-{[(5-methylpyrazin- 443.5 2-yl)methyl]amino}quinolin-2(1H)-one 591 4-[(3-amino-2-hydroxypropyl)amino]-3-(1H-benzimidazol-2-yl)- 410.4 6,7-dimethoxyquinolin-2(1H)-one 592 3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-[(2- 395.4 methoxyethyl)amino]quinolin-2(1H)-one 593 {[3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-2-oxo-1,2- 376.4 dihydroquinolin-4-yl]amino}acetonitrile 594 3-(1H-benzimidazol-2-yl)-4-{[2-(2- 425.5 hydroxyethoxy)ethyl]amino}-6,7-dimethoxyquinolin-2(1H)-one 595 3-(1H-benzimidazol-2-yl)-4-[(3R)-3-hydroxypyrrolidin-1-yl]- 407.4 6,7-dimethoxyquinolin-2(1H)-one 596 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 487.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzonitrile 597 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 506.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid 598 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 505.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzamide 599 methyl 3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 520.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoate 600 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[6- 587.1 (piperidin-3-yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)- one 601 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[3-(2- 488.0 oxopyrrolidin-1-yl)propyl]amino}quinolin-2(1H)-one 602 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2- 502.0 pyridin-2-ylethyl)amino]quinolin-2(1H)-one 603 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[3-(2- 522.0 oxopyrrolidin-1-yl)propyl]amino}quinolin-2(1H)-one 604 6-chloro-4-[(6-methoxypyridin-3-yl)amino]-3-(5-morpholin-4-yl- 504.0 1H-benzimidazol-2-yl)quinolin-2(1H)-one 605 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3- 516.0 pyridin-2-ylpropyl)amino]quinolin-2(1H)-one 606 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(pyridin- 473.9 4-ylamino)quinolin-2(1H)-one 607 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[6- 601.1 (piperidin-3-ylmethoxy)pyridin-3-yl]methyl}amino)quinolin- 2(1H)-one 608 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(pyridin- 473.9 2-ylamino)quinolin-2(1H)-one 609 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 548.1 benzimidazol-2-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-7- yl]piperidine-4-carboxylic acid 610 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 513.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]piperidine-4- carboxylic acid 611 3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 506.6 benzimidazol-2-yl)-2-oxo-1,2-dihydroquinolin-7-yl]benzoic acid 612 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[2- 430.5 (piperidin-4-yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)- one 613 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 455.4 2-yl)-6,7-dichloroquinolin-2(1H)-one 614 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-({[2- 587.1 (piperidin-4-yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)- one 615 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-(pyrazin- 474.9 2-ylamino)quinolin-2(1H)-one 616 4-amino-3-(6-thiomorpholin-4-yl-1H-benzimidazol-2- 378.5 yl)quinolin-2(1H)-one 617 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 550.7 2-yl)-6-fluoro-7-(3-pyridin-3-ylpyrrolidin-1-yl)quinolin-2(1H)- one 618 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 558.6 2-yl)-5-fluoro-6-[4-(methylsulfonyl)phenyl]quinolin-2(1H)-one 619 6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 522.6 (1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one 620 methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 538.6 benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 621 methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 553.6 (1H-benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 622 methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 538.6 benzimidazol-2-yl)-5-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 623 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 494.6 2-yl)-5-fluoro-6-(2-methylphenyl)quinolin-2(1H)-one 624 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 508.6 2-yl)-6-(2-ethylphenyl)-5-fluoroquinolin-2(1H)-one 625 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 510.6 2-yl)-5-fluoro-6-(2-methoxyphenyl)quinolin-2(1H)-one 626 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 549.4 2-yl)-6-(2,4-dichlorophenyl)-5-fluoroquinolin-2(1H)-one 627 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 524.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 628 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 523.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzamide 629 N-{3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 537.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]phenyl}acetamide 630 3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 524.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 631 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 494.6 2-yl)-7-fluoro-6-(2-methylphenyl)quinolin-2(1H)-one 632 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 620.7 2-yl)-7-(2-methyl-1H-imidazol-1-yl)-6-[4- (methylsulfonyl)phenyl]quinolin-2(1H)-one 633 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 599.7 benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]phenyl}acetamide 634 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 602.8 benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin- 6-yl]phenyl}acetamide 635 N-{3-[7-(3-acetyl-1H-pyrrol-1-yl)-4-[(3R)-1- 626.7 azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol-2-yl)-2- oxo-1,2-dihydroquinolin-6-yl]phenyl}acetamide 636 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 562.7 benzimidazol-2-yl)-7-(dimethylamino)-2-oxo-1,2- dihydroquinolin-6-yl]phenyl}acetamide 637 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 613.7 benzimidazol-2-yl)-7-(2-ethyl-1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]phenyl}acetamide 638 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 498.6 2-yl)-7-(2-ethyl-1H-imidazol-1-yl)-6-fluoroquinolin-2(1H)-one 639 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 512.6 2-yl)-6-fluoro-7-(2-isopropyl-1H-imidazol-1-yl)quinolin-2(1H)- one 640 1-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 513.5 benzimidazol-2-yl)-6-fluoro-2-oxo-1,2-dihydroquinolin-7-yl]- 1H-pyrrole-3-carboxylic acid 641 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 546.8 2-yl)-7-chloro-6-iodoquinolin-2(1H)-one 642 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.4 2-yl)-5-fluoro-6-iodoquinolin-2(1H)-one 643 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.4 2-yl)-7-fluoro-6-iodoquinolin-2(1H)-one 644 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2- 502.0 pyridin-3-ylethyl)amino]quinolin-2(1H)-one 645 4-{[4-(aminomethyl)benzyl]amino}-3-(1H-benzimidazol-2-yl)-7- 430.9 chloroquinolin-2(1H)-one 646 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[2- 382.9 (dimethylamino)ethyl]amino}quinolin-2(1H)-one 647 3-(1H-benzimidazol-2-yl)-4-(1,4′-bipiperidin-1′-yl)-7- 463.0 chloroquinolin-2(1H)-one 648 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[3-(4-methylpiperazin-1- 452.0 yl)propyl]amino}quinolin-2(1H)-one 649 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-piperidin-1- 422.9 ylethyl)amino]quinolin-2(1H)-one 650 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[3-(1H-imidazol-1- 419.9 yl)propyl]amino}quinolin-2(1H)-one 651 3-(1H-benzimidazol-2-yl)-7-chloro-4-(pyridin-3- 388.8 ylamino)quinolin-2(1H)-one 652 3-(1H-benzimidazol-2-yl)-7-chloro-4-(pyridin-4- 388.8 ylamino)quinolin-2(1H)-one 653 3-(1H-benzimidazol-2-yl)-7-chloro-4-({[6-(piperidin-3- 502.0 yloxy)pyridin-3-yl]methyl}amino)quinolin-2(1H)-one 654 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[3-(2-oxopyrrolidin-1- 436.9 yl)propyl]amino}quinolin-2(1H)-one 655 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 536.6 benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 656 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 535.6 benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6- yl]benzamide 657 6-(4-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 534.6 (1H-benzimidazol-2-yl)-7-methoxyquinolin-2(1H)-one 658 methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 550.6 benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 659 methyl 3-amino-4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 565.6 (1H-benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin- 6-yl]benzoate 660 N-{3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 549.6 benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6- yl]phenyl}acetamide 661 6-(3-acetylphenyl)-4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3- 534.6 (1H-benzimidazol-2-yl)-7-methoxyquinolin-2(1H)-one 662 methyl 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 550.6 benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 663 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 536.6 benzimidazol-2-yl)-7-methoxy-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 664 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 506.6 2-yl)-7-methoxy-6-(2-methylphenyl)quinolin-2(1H)-one 665 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 520.6 2-yl)-6-(2-ethylphenyl)-7-methoxyquinolin-2(1H)-one 666 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 522.6 2-yl)-7-methoxy-6-(2-methoxyphenyl)quinolin-2(1H)-one 667 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 561.5 2-yl)-6-(2,4-dichlorophenyl)-7-methoxyquinolin-2(1H)-one 668 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 491.6 2-yl)-7-[2-(dimethylamino)ethoxy]-6-fluoroquinolin-2(1H)-one 669 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 503.6 2-yl)-6-fluoro-7-[(2S)-pyrrolidin-2-ylmethoxy]quinolin-2(1H)- one 670 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 531.6 2-yl)-6-fluoro-7-[2-(2-oxopyrrolidin-1-yl)ethoxy]quinolin-2(1H)- one 671 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 624.7 2-yl)-6-fluoro-7-{[(2S)-1-(4-nitrophenyl)pyrrolidin-2- yl]methoxy}quinolin-2(1H)-one 672 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 531.6 2-yl)-6-fluoro-7-[(1-methylpiperidin-2-yl)methoxy]quinolin- 2(1H)-one 673 3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-{[2-(1- 448.5 methylpyrrolidin-2-yl)ethyl]amino}quinolin-2(1H)-one 674 3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-{[2- 443.5 (methylsulfonyl)ethyl]amino}quinolin-2(1H)-one 675 3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-4-[(2-morpholin-4-yl- 527.6 2-pyridin-3-ylethyl)amino]quinolin-2(1H)-one 676 7-[(2-aminoethyl)amino]-4-[(3R)-1-azabicyclo[2.2.2]oct-3- 462.5 ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)-one 677 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 581.7 2-yl-6-fluoro-7-(3-phenylthiomorpholin-4-yl)quinolin-2(1H)- one 678 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 581.7 2-yl-6-fluoro-7-(2-phenylthiomorpholin-4-yl)quinolin-2(1H)- one 679 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 587.7 2-yl)-6-fluoro-7-{[2-(phenylsulfonyl)ethyl]amino}quinolin- 2(1H)-one 680 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 525.6 2-yl)-6-fluoro-7-{[2-(methylsulfonyl)ethyl]amino}quinolin- 2(1H)-one 681 7-{[(2R)-2-aminopropyl]amino}-4-[(3R)-1-azabicyclo[2.2.2]oct- 476.6 3-ylamino]-3-(1H-benzimidazol-2-yl)-6-fluoroquinolin-2(1H)- one 682 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 609.7 2-yl)-6-flouro-7-[(2-moropholin-4-yl-2-pyridin-3- ylethyl)amino]quionolin-2(1H)-one 683 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 524.6 benzimidazol-2-yl)-7-fluoro-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 684 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 572.6 benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 685 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 586.7 benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 686 4-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 589.7 benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin- 6-yl]benzoic acid 687 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 600.7 benzimidazol-2-yl)-7-(2-ethyl-1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 688 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 586.7 benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 689 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 589.7 benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin- 6-yl]benzoic acid 690 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 507.1 4[(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one 691 3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 572.6 benzimidazol-2-yl)-7-(1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 692 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 507.1 4-[(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one 693 3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 586.7 benzimidazol-2-yl)-7-(2-methyl-1H-imidazol-1-yl)-2-oxo-1,2- dihydroquinolin-6-yl]benzoic acid 694 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 493.0 4-[(pyrrolidin-2-ylmethyl)amino]quinolin-2(1H)-one 695 3-[4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 589.7 benzimidazol-2-yl)-2-oxo-7-piperidin-1-yl-1,2-dihydroquinolin- 6-yl]benzoic acid 696 4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-[5-(4- 481.0 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 697 4-{[(2S)-2-amino-3-methylbutyl]amino}-6-chloro-3-[5-(4- 495.0 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 698 4-{[(1S)-2-amino-1-benzylethyl]amino}-6-chloro-3-[5-(4- 543.1 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 699 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-[5-(4- 519.1 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 700 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 493.0 4-(piperidin-3-ylamino)quinolin-2(1H)-one 701 6-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-[5-(4- 481.0 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 702 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 480.0 (piperidin-4-ylamino)quinolin-2(1H)-one 703 4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(1H-benzimidazol-2- 408.9 yl)-7-chloroquinolin-2(1H)-one 704 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(3-morpholin-4- 438.9 ylpropyl)amino]quinolin-2(1H)-one 705 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(pyridin-3- 402.9 ylmethyl)amino]quinolin-2(1H)-one 706 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-pyridin-3- 416.9 ylethyl)amino]quinolin-2(1H)-one 707 4-{[(1R,2R)-2-aminocyclohexyl]amino}-7-chloro-3-(5- 494.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 708 4-[(4-aminocyclohexyl)amino]-7-chloro-3-(5-morpholin-4-yl- 494.0 1H-benzimidazol-2-yl)quinolin-2(1H)-one 709 7-chloro-4-{[2-(methylamino)ethyl]amino}-3-(5-morpholin-4-yl- 453.9 1H-benzimidazol-2-yl)quinolin-2(1H)-one 710 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 480.0 [(pyrrolidin-2-ylmethyl)amino]quinolin-2(1H)-one 711 4-{[(1S)-2-amino-1-benzylethyl]amino}-7-chloro-3-(5- 530.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 712 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 466.0 (pyrrolidin-3-ylamino)quinolin-2(1H)-one 713 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-pyrrolidin-1- 408.9 ylethyl)amino]quinolin-2(1H)-one 714 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-piperidin-2- 422.9 ylethyl)amino]quinolin-2(1H)-one 715 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(piperidin-3- 408.9 ylmethyl)amino]quinolin-2(1H)-one 716 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(piperidin-4- 408.9 ylmethyl)amino]quinolin-2(1H)-one 717 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[(2-methyl-1-piperidin-4- 539.1 yl-1H-benzimidazol-5-yl)methyl]amino}quinolin-2(1H)-one 718 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-7- 408.9 chloroquinolin-2(1H)-one 719 3-(1H-benzimidazol-2-yl)-7-chloro-4-(pyrrolidin-3- 380.8 ylamino)quinolin-2(1H)-one 720 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.6 2-yl)-6-[4-(trifluoromethyl)phenyl]quinolin-2(1H)-one 721 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 530.6 2-yl)-6-[3-(trifluoromethyl)phenyl]quinolin-2(1H)-one 722 4-amino-5-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H- 421.5 benzimidazol-2-yl]quinolin-2(1H)-one 723 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[(2S)- 480.0 pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one 724 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-{[(2R)- 480.0 pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one 725 7-chloro-4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-(5- 508.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 726 7-chloro-4-({[(2R)-1-ethylpyrrolidin-2-yl]methyl}amino)-3-(5- 508.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 727 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-chloro-3-(5- 506.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 728 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 494.0 [(piperidin-3-ylmethyl)amino]quinolin-2(1H)-one 729 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 494.0 [(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one 730 4-{[(2S)-2-amino-3-methylbutyl]amino}-7-chloro-3-(5- 482.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 731 4-{[4-(aminomethyl)benzyl]amino}-7-chloro-3-(5-morpholin-4- 516.0 yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 732 4-{[(1R)-1-(aminomethyl)propyl]amino}-7-chloro-3-(5- 468.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 733 7-choro-4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-(5- 537.1 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 734 7-chloro-4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-(5- 505.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 735 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(2- 494.0 pyrrolidin-1-ylethyl)amino]quinolin-2(1H)-one 736 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 494.0 [(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one 737 7-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-(5-morpholin-4- 468.0 yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 738 7-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3S)- 466.0 pyrrolidin-3-ylamino]quinolin-2(1H)-one 739 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 478.6 2-yl)-6-(4-hydroxyphenyl)quinolin-2(1H)-one 740 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 478.6 2-yl)-6-(3-hydroxyphenyl)quinolin-2(1H)-one 741 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 478.6 2-yl)-6-(2-hydroxyphenyl)quinolin-2(1H)-one 742 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[(2S)-pyrrolidin-2- 394.9 ylmethyl]amino}quinolin-2(1H)-one 743 3-(1H-benzimidazol-2-yl)-7-chloro-4-({[(2S)-1-ethylpyrrolidin- 422.9 2-yl]methyl}amino)quinolin-2(1H)-one 744 3-(1H-benzimidazol-2-yl)-7-chloro-4-({[(2R)-1-ethylpyrrolidin- 422.9 2-yl]methyl}amino)quinolin-2(1H)-one 745 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(3S)-pyrrolidin-3- 380.8 ylamino]quinolin-2(1H)-one 746 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2S)-pyrrolidin-2- 394.9 ylmethyl]amino}quinolin-2(1H)-one 747 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2R)-pyrrolidin-2- 394.9 ylmethyl]amino}quinolin-2(1H)-one 748 3-(1H-benzimidazol-2-yl)-6-chloro-4-({[(2S)-1-ethylpyrrolidin- 422.9 2-yl]methyl}amino)quinolin-2(1H)-one 749 3-(1H-benzimidazol-2-yl)-6-chloro-4-({[(2R)-1-ethylpyrrolidin- 422.9 2-yl]methyl}amino)quinolin-2(1H)-one 750 4-amino-3-[5-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol- 380.8 2-yl]quinolin-2(1H)-one 751 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-bromo-3-(5- 550.5 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 752 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-7-bromo-3-(6- 495.4 methoxy-1H-benzimidazol-2-yl)quinolin-2(1H)-one 753 3-{[3-(1H-benzimidazol-2-yl)-6,7-dimethoxy-2-oxo-1,2- 474.5 dihydroquinolin-4-yl]amino}bicyclo[2.2.1]heptane-2- carboxamide 754 4-[(3-amino-2,2-dimethylpropyl)amino]-3-(1H-benzimidazol-2- 422.5 yl)-6,7-dimethoxyquinolin-2(1H)-one 755 3-(1H-benzimidazol-2-yl)-4-{[3-(dimethylamino)-2,2- 450.6 dimethylpropyl]amino}-6,7-dimethoxyquinolin-2(1H)-one 756 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(pyridin-2- 402.9 ylmethyl)amino]quinolin-2(1H)-one 757 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(2-pyridin-2- 416.9 ylethyl)amino]quinolin-2(1H)-one 758 3-(1H-benzimidazol-2-yl)-7-chloro-4-{[2- 368.8 (methylamino)ethyl]amino}quinolin-2(1H)-one 759 3-(1H-benzimidazol-2-yl)-7-chloro-4-[(piperidin-2- 408.9 ylmethyl)amino]quinolin-2(1H)-one 760 3-(1H-benzimidazol-2-yl)-7-chloro-4-(piperidin-4- 394.9 ylamino)quinolin-2(1H)-one 761 4-amino-3-[5-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol- 471.6 2-yl]quinolin-2(1H)-one 762 4-amino-3-{5-[(3S)-3-(dimethylnitroryl)pyrrolidin-1-yl]-1H- 405.5 benzimidazol-2-yl}quinolin-2(1H)-one 763 4-amino-3-(5-{2-[(dimethylamino)methyl]morpholin-4-yl}-1H- 419.5 benzimidazol-2-yl)quinolin-2(1H)-one 764 methyl 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 534.6 benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6- yl]benzoate 765 3-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 520.6 benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 766 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 519.6 benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6- yl]benzamide 767 4-[4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 520.6 benzimidazol-2-yl)-5-methyl-2-oxo-1,2-dihydroquinolin-6- yl]benzoic acid 768 4-amino-3-{5-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]- 429.5 1H-benzimidazol-2-yl}quinolin-2(1H)-one 769 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl- 449.5 N-(1-methylpiperidin-4-yl)-1H-benzimidazole-6-carboxamide 770 4-amino-3-(1H-benzimidazol-2-yl)-5-[(1-methylpiperidin-4- 390.5 yl)oxy]quinolin-2(1H)-one 771 4-amino-5-(1-azabicyclo[2.2.2]oct-3-yloxy)-3-(1H- 402.5 benzimidazol-2-yl)quinolin-2(1H)-one 772 4-amino-5-fluoro-3-{6-[(2-piperidin-1-ylethyl)amino]-1H- 421.5 benzimidazol-2-yl}quinolin-2(1H)-one 773 4,6-diamino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 390.5 yl]quinolin-2(1H)-one 774 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 339.3 benzimidazole-5-carboxylic acid 775 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-pyridin-3-yl-1H- 397.4 benzimidazole-5-carboxamide 776 4-amino-3-(5-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H- 390.4 benzimidazol-2-yl)quinolin-2(1H)-one 777 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 432.5 yl]-2-oxo-1,2-dihydroquinolin-6-yl}acetamide 778 4-amino-5-fluoro-3-(6-morpholin-4-yl-1H-benzimidazol-2- 380.4 yl)quinolin-2(1H)-one 779 3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2- 396.9 (dimethylamino)ethyl]amino}-6-methylquinolin-2(1H)-one 780 4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(5-chloro-1H- 422.9 benzimidazol-2-yl)-6-methylquinolin-2(1H)-one 781 3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-3- 422.9 ylmethyl)amino]quinolin-2(1H)-one 782 3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-4- 422.9 ylmethyl)amino]quinolin-2(1H)-one 783 4-[(4-aminocyclohexyl)amino]-3-(5-chloro-1H-benzimidazol-2- 422.9 yl)-6-methylquinolin-2(1H)-one 784 3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-{[2- 382.9 (methylamino)ethyl]amino}quinolin-2(1H)-one 785 3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-(pyrrolidin-3- 394.9 ylamino)quinolin-2(1H)-one 786 3-(5-chloro-1H-benzimidazol-2-yl)-6-methyl-4-[(piperidin-2- 422.9 ylmethyl)amino]quinolin-2(1H)-one 787 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H- 434.9 benzimidazol-2-yl)-6-methylquinolin-2(1H)-one 788 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H- 434.9 benzimidazol-2-yl)-6-methylquinolin-2(1H)-one 789 4-amino-3-(6-{(2R,5R)-2-[(dimethylamino)methyl]-5- 433.5 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)- one 790 4-amino-3-(5-{[(3R)-3-hydroxypiperidin-1-yl]carbonyl}-1H- 404.4 benzimidazol-2-yl)quinolin-2(1H)-one 791 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-(2-piperidin-1- 431.5 ylethyl)-1H-benzimidazole-5-carboxamide 792 4-amino-3-[5-(piperazin-1-ylcarbonyl)-1H-benzimidazol-2- 389.4 yl]quinolin-2(1H)-one 793 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 474.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2,2-dimethylpropanamide 794 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 522.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-3-phenylpropanamide 795 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 538.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-(benzyloxy)acetamide 796 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 514.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-thien-2-ylacetamide 797 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 484.5 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-furamide 798 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-(2-pyrrolidin-1- 417.5 ylethyl)-1H-benzimidazole-5-carboxamide 799 ethyl (4-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 475.5 benzimidazol-5-yl]carbonyl}piperazin-1-yl)acetate 800 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 509.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-phenylurea 801 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 523.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-benzylurea 802 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 537.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(2-phenylethyl)urea 803 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 494.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}benzamide 804 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-piperidin-3-yl- 403.5 1H-benzimidazole-5-carboxamide 805 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3R)-1- 429.5 azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide 806 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[2- 447.6 (diethylamino)ethyl]-N-ethyl-1H-benzimidazole-5-carboxamide 807 4-amino-3-[6-(pyridin-4-yloxy)-1H-benzimidazol-2-yl]quinolin- 370.4 2(1H)-one 808 4-amino-5-fluoro-3-{6-[(4-methylpiperazin-1-yl)carbonyl]-1H- 421.4 benzimidazol-2-yl}quinolin-2(1H)-one 809 4-amino-5-fluoro-3-{6-[(4-isopropylpiperazin-1-yl)carbonyl]- 449.5 1H-benzimidazol-2-yl}quinolin-2(1H)-one 810 4-amino-3-{6-[(4-cyclohexylpiperazin-1-yl)carbonyl]-1H- 489.6 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 811 4-amino-6-(isobutylamino)-3-[6-(4-methylpiperazin-1-yl)-1H- 446.6 benzimidazol-2-yl]quinolin-2(1H)-one 812 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl- 488.6 N-(1-methylpyrrolidin-3-yl)-1H-benzimidazole-6-carboxamide 813 4-amino-6-[(2-methylbutyl)amino]-3-[6-(4-methylpiperazin-1- 460.6 yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 814 4-amino-6-[(cyclohexylmethyl)amino]-3-[6-(4-methylpiperazin- 486.6 1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 815 4-amino-3-(6-{[(3S)-3-methylpiperazin-1-yl]carbonyl}-1H- 403.5 benzimidazol-2-yl)quinolin-2(1H)-one 816 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3S)-1- 429.5 azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide 817 4-amino-3-[6-(1,4′-bipiperidin-1′-ylcarbonyl)-1H-benzimidazol- 489.6 2-yl]-5-fluoroquinolin-2(1H)-one 818 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl- 435.5 N-(1-methylpyrrolidin-3-yl)-1H-benzimidazole-6-carboxamide 819 4-amino-3-(1H-benzimidazol-2-yl)-5-[(4- 415.5 methoxyphenyl)thio]quinolin-2(1H)-one 820 4-amino-3-(1H-benzimidazol-2-yl)-5-[(4- 447.5 methoxyphenyl)sulfonyl]quinolin-2(1H)-one 821 4-amino-3-(1H-benzimidazol-2-yl)-5-[(2- 415.5 methoxyphenyl)thio]quinolin-2(1H)-one 822 N-(4-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 426.4 benzimidazol-5-yl]oxy}phenyl)acetamide 823 4-amino-6-(benzylamino)-3-[6-(4-methylpiperazin-1-yl)-1H- 480.6 benzimidazol-2-yl]quinolin-2(1H)-one 824 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 578.7 {[(3-phenoxythien-2-yl)methyl]amino}quinolin-2(1H)-one 825 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 500.6 {[(3-methylthien-2-yl)methyl]amino}quinolin-2(1H)-one 826 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 487.6 [(1,3-thiazol-2-ylmethyl)amino]quinolin-2(1H)-one 827 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 482.6 [(pyrazin-2-ylmethyl)amino]quinolin-2(1H)-one 828 4-amino-3-(5-{2-[(dimethylamino)methyl]-1,4-oxazepan-4-yl}- 433.5 1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one 829 4-amino-3-(5-{2-[(dimethylamino)methyl]-1,4-oxazepan-4-yl}- 451.5 1H-benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one 830 6-chloro-4-{[2-(dimethylamino)-2-pyridin-3-ylethyl]amino}-3- 545.1 (5-morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 831 6-amino-4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H- 401.5 benzimidazol-2-yl)quinolin-2(1H)-one 832 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2- 417.3 (dimethylamino)ethyl]amino}quinolin-2(1H)-one 833 4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(5-chloro- 443.3 1H-benzimidazol-2-yl)quinolin-2(1H)-one 834 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(piperidin-3- 443.3 ylmethyl)amino]quinolin-2(1H)-one 835 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(piperidin-4- 443.3 ylmethyl)amino]quinolin-2(1H)-one 836 4-[(4-aminocyclohexyl)amino]-6-chloro-3-(5-chloro-1H- 443.3 benzimidazol-2-yl)quinolin-2(1H)-one 837 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2- 403.3 (methylamino)ethyl]amino}quinolin-2(1H)-one 838 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-(pyrrolidin-3- 415.3 ylamino)quinolin-2(1H)-one 839 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(piperidin-2- 443.3 ylmethyl)amino]quinolin-2(1H)-one 840 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-chloro- 455.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 841 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(5-chloro- 455.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 842 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 473.6 {[(2S)-pyrrolidin-2-ylmethyl]amino}quinolin-2(1H)-one 843 4-amino-6-{[(5-methylisoxazol-3-yl)methyl]amino}-3-[6-(4- 485.6 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 844 4-amino-3-(5-{(2S,5R)-2-[(dimethylamino)methyl]-5- 433.5 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)- one 845 3-(5-chloro-1H-benzimidazol-2-yl)-4-{[2- 418.8 (dimethylamino)ethyl]amino}-6,7-difluoroquinolin-2(1H)-one 846 4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(5-chloro-1H- 444.9 benzimidazol-2-yl)-6,7-difluoroquinolin-2(1H)-one 847 3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-3- 444.9 ylmethyl)amino]quinolin-2(1H)-one 848 3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-4- 444.9 ylmethyl)amino]quinolin-2(1H)-one 849 4-[(4-aminocyclohexyl)amino]-3-(5-chloro-1H-benzimidazol-2- 444.9 yl)-6,7-difluoroquinolin-2(1H)-one 850 3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-{[2- 404.8 (methylamino)ethyl]amino}quinolin-2(1H)-one 851 3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-(pyrrolidin-3- 416.8 ylamino)quinolin-2(1H)-one 852 3-(5-chloro-1H-benzimidazol-2-yl)-6,7-difluoro-4-[(piperidin-2- 444.9 ylmethyl)amino]quinolin-2(1H)-one 853 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H- 456.9 benzimidazol-2-yl)-6,7-difluoroquinolin-2(1H)-one 854 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(5-chloro-1H- 456.9 benzimidazol-2-yl)-6,7-difluoroquinolin-2(1H)-one 855 4-amino-3-(6-{[(3R)-3-methylpiperazin-1-yl]carbonyl}-1H- 403.5 benzimidazol-2-yl)quinolin-2(1H)-one 856 4-amino-3-(5-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-1H- 390.4 benzimidazol-2-yl)quinolin-2(1H)-one 857 4-amino-3-(5-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1H- 433.5 benzimidazol-2-yl)quinolin-2(1H)-one 858 4-amino-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2- 433.5 yl]-5-methoxyquinolin-2(1H)-one 859 4-amino-3-(5-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H- 403.5 benzimidazol-2-yl)quinolin-2(1H)-one 860 4-amino-3-(5-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H- 421.5 benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one 861 4-amino-3-(6-{(2R,5S)-2-[(dimethylamino)methyl]-5- 433.5 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)quinolin-2(1H)- one 862 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 473.6 (piperidin-4-ylamino)quinolin-2(1H)-one 863 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 479.0 4-[(3S)-pyrrolidin-3-ylamino]quinolin-2(1H)-one 864 4-amino-3-{5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 407.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 865 4-amino-3-{5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 407.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 866 4-amino-3-[6-(2,6-dimethylmorpholin-4-yl)-1H-benzimidazol-2- 408.4 yl]-5-fluoroquinolin-2(1H)-one 867 4-amino-3-{6-[(3-aminopyrrolidin-1-yl)carbonyl]-1H- 389.4 benzimidazol-2-yl}quinolin-2(1H)-one 868 ethyl (3S,4R)-4-({[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)- 505.5 1H-benzimidazol-6-yl]carbonyl}amino)-3-methoxypiperidine-1- carboxylate 869 6-amino-3-(1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin-3- 361.4 ylamino]quinolin-2(1H)-one 870 4-amino-3-(6-{(2R,5S)-2-[(dimethylamino)methyl]-5- 451.5 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin- 2(1H)-one 871 N-{(3S)-1-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 417.5 benzimidazol-6-yl]pyrrolidin-3-yl}-N-methylacetamide 872 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-piperidin-4-yl- 403.5 1H-benzimidazole-6-carboxamide 873 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-[2-(1- 431.5 methylpyrrolidin-2-yl)ethyl]-1H-benzimidazole-6-carboxamide 874 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 475.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-isopropylurea 875 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 537.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(3,5-dimethylphenyl)urea 876 N-allyl-N′-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H- 473.6 benzimidazol-2-yl]-2-oxo-1,2-dihydroquinolin-6-yl}urea 877 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 489.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(tert-butyl)urea 878 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 555.7 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-[2- (methylthio)phenyl]urea 879 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 502.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}heptanamide 880 4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 460.6 (neopentylamino)quinolin-2(1H)-one 881 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 578.5 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(3,4-dichlorophenyl)urea 882 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 577.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-[3- (trifluoromethyl)phenyl]urea 883 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 531.7 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-heptylurea 884 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 553.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-N′-(2-ethoxyphenyl)urea 885 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 460.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-2-methylpropanamide 886 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 522.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-4-ethylbenzamide 887 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 519.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}-4-cyanobenzamide 888 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 500.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}cyclohexanecarboxamide 889 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 496.5 yl]-2-oxo-1,2-dihydroquinolin-6-yl}pyrazine-2-carboxamide 890 N-{4-amino-3-[6-(4-methylpiperazinyl)benzimidazol-2-yl]-2- 537.6 oxo(6-hydroquinolyl)}-2-[benzylamino]acetamide 891 4-amino-6-[methyl(1-methylpiperidin-4-yl)amino]-3-[6-(4- 501.6 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 892 4-amino-6-[({5-[(dimethylamino)methyl]-2- 527.6 furyl}methyl)amino]-3-[6-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]quinolin-2(1H)-one 893 4-amino-6-{[(2-ethyl-5-methyl-4H-imidazol-4- 512.6 yl)methyl]amino}-3-[6-(4-methylpiperazin-1-yl)-1H- benzimidazol-2-yl]quinolin-2(1H)-one 894 N-{4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2- 460.6 yl]-2-oxo-1,2-dihydroquinolin-6-yl}butanamide 895 4-amino-3-(5-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1- 457.5 yl]carbonyl}-1H-benzimidazol-2-yl)quinolin-2(1H)-one 896 4-amino-3-[5-({(2R,5R)-2-[(dimethylamino)methyl]-5- 461.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2- yl]quinolin-2(1H)-one 897 4-amino-3-[5-({(2S,5R)-2-[(dimethylamino)methyl]-5- 461.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2- yl]quinolin-2(1H)-one 898 4-amino-5-fluoro-3-(6-{[(3S)-3-methylpiperazin-1-yl]carbonyl}- 421.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 899 4-amino-5-fluoro-3-(6-{[(3R)-3-methylpiperazin-1-yl]carbonyl}- 421.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 900 4-amino-5-fluoro-3-(5-{[(2R)-2-(pyrrolidin-1- 475.5 ylmethyl)pyrrolidin-1-yl]carbonyl}-1H-benzimidazol-2- yl)quinolin-2(1H)-one 901 4-amino-6-(dimethylamino)-3-[5-(4-methylpiperazin-1-yl)-1H- 418.5 benzimidazol-2-yl]quinolin-2(1H)-one 902 4-amino-6-(methylamino)-3-[5-(4-methylpiperazin-1-yl)-1H- 404.5 benzimidazol-2-yl]quinolin-2(1H)-one 903 4-amino-5-fluoro-3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H- 411.4 benzimidazol-2-yl]quinolin-2(1H)-one 904 4-amino-3-[6-({(2R,5S)-2-[(dimethylamino)methyl]-5- 461.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2- yl]quinolin-2(1H)-one 905 4-amino-3-[6-({(2S,5S)-2-[(dimethylamino)methyl]-5- 461.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2- yl]quinolin-2(1H)-one 906 4-amino-3-{6-[(3,5-dimethylpiperazin-1-yl)carbonyl]-1H- 417.5 benzimidazol-2-yl}quinolin-2(1H)-one 907 4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5- 407.5 fluoroquinolin-2(1H)-one 908 4-amino-3-[6-({(2R,5S)-2-[(dimethylamino)methyl]-5- 479.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5- fluoroquinolin-2(1H)-one 909 4-amino-3-[6-({(2S,5S)-2-[(dimethylamino)methyl]-5- 479.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5- fluoroquinolin-2(1H)-one 910 4-amino-3-[5-({(2R,5R)-2-[(dimethylamino)methyl]-5- 479.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5- fluoroquinolin-2(1H)-one 911 4-amino-3-[5-({(2S,5R)-2-[(dimethylamino)methyl]-5- 479.5 methylmorpholin-4-yl}carbonyl)-1H-benzimidazol-2-yl]-5- fluoroquinolin-2(1H)-one 912 N-[3-({4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol- 524.6 2-yl]-2-oxo-1,2-dihydroquinolin-5-yl}oxy)phenyl]acetamide 913 4-amino-3-{6-[(4-ethylpiperazin-1-yl)carbonyl]-1H- 417.5 benzimidazol-2-yl}quinolin-2(1H)-one 914 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N,N′-dimethyl-1H- 363.4 benzimidazole-6-carbohydrazide 915 2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-N-(tetrahydrofuran- 404.4 2-ylmethyl)-1H-benzimidazole-6-carboxamide 916 4-amino-5-[3-(dimethylamino)phenoxy]-3-[6-(4- 510.6 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 917 4-amino-5-(4-aminophenoxy)-3-[6-(4-methylpiperazin-1-yl)-1H- 482.6 benzimidazol-2-yl]quinolin-2(1H)-one 918 6-chloro-4-{[2-(dimethylamino)ethyl]amino}-3-(6-fluoro-1H- 400.9 benzimidazol-2-yl)quinolin-2(1H)-one 919 4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(6-fluoro- 426.9 1H-benzimidazol-2-yl)quinolin-2(1H)-one 920 6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-3- 426.9 ylmethyl)amino]quinolin-2(1H)-one 921 6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-4- 426.9 ylmethyl)amino]quinolin-2(1H)-one 922 4-[(4-aminocyclohexyl)amino]-6-chloro-3-(6-fluoro-1H- 426.9 benzimidazol-2-yl)quinolin-2(1H)-one 923 6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-{[2- 386.8 (methylamino)ethyl]amino}quinolin-2(1H)-one 924 6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin- 398.8 3-ylamino]quinolin-2(1H)-one 925 6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3R)-pyrrolidin- 398.8 3-ylamino]quinolin-2(1H)-one 926 6-chloro-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-2- 426.9 ylmethyl)amino]quinolin-2(1H)-one 927 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-fluoro- 438.9 1H-benzimidazol-2-yl)quinolin-2(1H)-one 928 6-bromo-4-{[2-(dimethylamino)ethyl]amino}-3-(6-fluoro-1H- 445.3 benzimidazol-2-yl)quinolin-2(1H)-one 929 4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-bromo-3-(6-fluoro- 471.3 1H-benzimidazol-2-yl)quinolin-2(1H)-one 930 6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-3- 471.3 ylmethyl)amino]quinolin-2(1H)-one 931 6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-4- 471.3 ylmethyl)amino]quinolin-2(1H)-one 932 4-[(4-aminocyclohexyl)amino]-6-bromo-3-(6-fluoro-1H- 471.3 benzimidazol-2-yl)quinolin-2(1H)-one 933 6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-{[2- 431.3 (methylamino)ethyl]amino}quinolin-2(1H)-one 934 6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin- 443.3 3-ylamino]quinolin-2(1H)-one 935 6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(piperidin-2- 471.3 ylmethyl)amino]quinolin-2(1H)-one 936 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylaminol]-6-bromo-3-(6-fluoro- 483.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 937 6-bromo-3-(6-fluoro-1H-benzimidazol-2-yl)-4-[(3R)-pyrrolidin- 443.3 3-ylamino]quinolin-2(1H)-one 938 N-[4-({4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol- 524.6 2-yl]-2-oxo-1,2-dihydroquinolin-5-yl}oxy)phenyl]acetamide 939 4-amino-3-{6-[(4-ethylpiperazin-1-yl)carbonyl]-1H- 435.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 940 ethyl (3S,4R)-4-({[2-(4-amino-5-fluoro-2-oxo-1,2- 523.5 dihydroquinolin-3-yl)-1H-benzimidazol-6-yl]carbonyl}amino)-3- methoxypiperidine-1-carboxylate 941 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3R)-1- 447.5 azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide 942 2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-[(3S)-1- 447.5 azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-6-carboxamide 943 4-amino-5-fluoro-3-{5-[(5-methyl-2,5-diazabicyclo[2.2.1]hept-2- 433.5 yl)carbonyl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one 944 4-amino-3-[5-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-5- 461.6 fluoroquinolin-2(1H)-one 945 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(7- 506.0 morpholin-4-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one 946 6-chloro-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-4- 480.0 (piperidin-4-ylamino)quinolin-2(1H)-one 947 6-chloro-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3S)- 466.0 pyrrolidin-3-ylamino]quinolin-2(1H)-one 948 4-amino-7-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H- 393.4 benzimidazol-2-yl]quinolin-2(1H)-one 949 4-amino-3-{6-[(2,6-dimethylpiperazin-1-yl)carbonyl]-1H- 417.5 benzimidazol-2-yl}quinolin-2(1H)-one 950 4-amino-3-(5-{(2S,5R)-2-[(dimethylamino)methyl]-5- 451.5 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin- 2(1H)-one 951 6-chloro-3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-4-[(3S)- 466.0 pyrrolidin-3-ylamino]quinolin-2(1H)-one 952 4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5- 451.5 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin- 2(1H)-one 953 4-amino-3-(1H-benzimidazol-2-yl)-6-[methyl(1-methylpiperidin- 403.5 4-yl)amino]quinolin-2(1H)-one 954 4-amino-6-[isobutyl(methyl)amino]-3-[6-(4-methylpiperazin-1- 460.6 yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 955 4-amino-6-[(cyclohexylmethyl)(methyl)amino]-3-[6-(4- 500.7 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 956 4,6-diamino-3-(6,7-dimethyl-1H-benzimidazol-2-yl)quinolin- 320.4 2(1H)-one 957 4-amino-3-(6,7-dimethyl-1H-benzimidazol-2-yl)-6- 334.4 (methylamino)quinolin-2(1H)-one 958 4-amino-3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6- 334.4 (methylamino)quinolin-2(1H)-one 959 4,6-diamino-3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one 292.3 960 4-amino-3-(6,7-dimethyl-1H-benzimidazol-2-yl)-6- 376.5 (isobutylamino)quinolin-2(1H)-one 961 4-amino-3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6- 376.5 (isobutylamino)quinolin-2(1H)-one 962 N-(3-{[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 426.4 benzimidazol-6-yl]oxy}phenyl)acetamide 963 4-amino-3-[6-(3,4-dimethylpiperazin-1-yl)-1H-benzimidazol-2- 389.5 yl]quinolin-2(1H)-one 964 N-[3-({4-amino-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol- 524.6 2-yl]-2-oxo-1,2-dihydroquinolin-6-yl}oxy)phenyl]acetamide 965 4-amino-3-(6-{(2R,5R)-2-[(dimethylamino)methyl]-5- 451.5 methylmorpholin-4-yl}-1H-benzimidazol-2-yl)-5-fluoroquinolin- 2(1H)-one 966 4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-bromo-3-(6-chloro-5- 505.8 fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one 967 6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4- 505.8 [(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one 968 4-[(4-aminocyclohexyl)amino]-6-bromo-3-(6-chloro-5-fluoro- 505.8 1H-benzimidazol-2-yl)quinolin-2(1H)-one 969 6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-{[2- 465.7 (methylamino)ethyl]amino}quinolin-2(1H)-one 970 6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4- 477.7 (pyrrolidin-3-ylamino)quinolin-2(1H)-one 971 6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-[(3R)- 477.7 pyrrolidin-3-ylamino]quinolin-2(1H)-one 972 6-bromo-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4- 505.8 [(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one 973 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-bromo-3-(6-chloro- 517.8 5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one 974 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-bromo-3-(6-chloro- 517.8 5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one 975 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-bromo-3-(6-fluoro- 483.4 1H-benzimidazol-2-yl)quinolin-2(1H)-one 976 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-fluoro- 438.9 1H-benzimidazol-2-yl)quinolin-2(1H)-one 977 4-amino-6-[bis(cyclohexylmethyl)amino]-3-(6,7-dimethyl-1H- 512.7 benzimidazol-2-yl)quinolin-2(1H)-one 978 4-amino-6-[bis(cyclohexylmethyl)amino]-3-(5,6-dimethyl-1H- 512.7 benzimidazol-2-yl)quinolin-2(1H)-one 979 4-amino-5-(methylamino)-3-[6-(4-methylpiperazin-1-yl)-1H- 404.5 benzimidazol-2-yl]quinolin-2(1H)-one 980 4-amino-6-[(cyclohexylmethyl)amino]-3-(6,7-dimethyl-1H- 416.5 benzimidazol-2-yl)quinolin-2(1H)-one 981 4-amino-6-[(cyclohexylmethyl)amino]-3-(5,6-dimethyl-1H- 416.5 benzimidazol-2-yl)quinolin-2(1H)-one 982 4-amino-6,7-difluoro-3-[5-(4-methylpiperazin-1-yl)-1H- 411.4 benzimidazol-2-yl]quinolin-2(1H)-one 983 4-amino-5-fluoro-3-[6-(2-methylpiperazin-1-yl)-1H- 393.4 benzimidazol-2-yl]quinolin-2(1H)-one 984 4-amino-7-fluoro-3-{6-[(4-isopropylpiperazin-1-yl)carbonyl]- 449.5 1H-benzimidazol-2-yl}quinolin-2(1H)-one 985 4-amino-3-[6-(2,4-dimethylpiperazin-1-yl)-1H-benzimidazol-2- 407.5 yl]-5-fluoroquinolin-2(1H)-one 986 2-(4-amino-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-N-methyl- 449.5 N-(1-methylpiperidin-4-yl)-1H-benzimidazole-5-carboxamide 987 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(3S)-pyrrolidin- 415.3 3-ylamino]quinolin-2(1H)-one 988 4-amino-7-fluoro-3-(5-{[(2R)-2-(pyrrolidin-1- 475.5 ylmethyl)pyrrolidin-1-yl]carbonyl}-1H-benzimidazol-2- yl)quinolin-2(1H)-one 989 4-amino-3-{6-[4-(2-methoxyethyl)piperazin-1-yl]-1H- 419.5 benzimidazol-2-yl}quinolin-2(1H)-one 990 4-amino-3-[5-(methylamino)-1H-benzimidazol-2-yl]quinolin- 306.3 2(1H)-one 991 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 493.0 4-{[(3S)-1-methylpyrrolidin-3-yl]amino}quinolin-2(1H)-one 992 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-{[(3S)-1- 429.3 methylpyrrolidin-3-yl]amino}quinolin-2(1H)-one 993 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(3S)-1-methylpyrrolidin- 394.9 3-yl]amino}quinolin-2(1H)-one 994 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(1-methylpiperidin-4- 408.9 yl)amino]quinolin-2(1H)-one 995 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(1- 443.3 methylpiperidin-4-yl)amino]quinolin-2(1H)-one 996 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 507.1 4-[(1-methylpiperidin-4-yl)amino]quinolin-2(1H)-one 997 6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]- 521.1 4-{[(1-methylpiperidin-2-yl)methyl]amino}quinolin-2(1H)-one 998 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-{5- 547.1 [methyl(1-methylpiperidin-4-yl)amino]-1H-benzimidazol-2- yl}quinolin-2(1H)-one 999 6-chloro-3-{5-[methyl(1-methylpiperidin-4-yl)amino]-1H- 521.1 benzimidazol-2-yl}-4-(piperidin-4-ylamino)quinolin-2(1H)-one 1000 6-chloro-3-{5-[methyl(1-methylpiperidin-4-yl)amino]-1H- 507.1 benzimidazol-2-yl}-4-[(3S)-pyrrolidin-3-ylamino]quinolin- 2(1H)-one 1001 4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-{5-[methyl(1- 509.1 methylpiperidin-4-yl)amino]-1H-benzimidazol-2-yl}quinolin- 2(1H)-one 1002 4-amino-3-{6-[(3S)-3,4-dimethylpiperazin-1-yl]-1H- 389.5 benzimidazol-2-yl}quinolin-2(1H)-one 1003 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2- 400.5 oxo-1,2-dihydroquinoline-6-carbonitrile 1004 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2- 419.5 oxo-1,2-dihydroquinoline-6-carboxylic acid 1005 4-amino-5-fluoro-3-{5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin- 419.5 2(1H)-yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one 1006 4-amino-3-{6-[(3S)-3,4-dimethylpiperazin-1-yl]-1H- 407.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 1007 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-{6-[(3R)- 533.1 3-(dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2- yl}quinolin-2(1H)-one 1008 6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 507.1 benzimidazol-2-yl}-4-(piperidin-4-ylamino)quinolin-2(1H)-one 1009 6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 493.0 benzimidazol-2-yl}-4-[(3S)-pyrrolidin-3-ylamino]quinolin- 2(1H)-one 1010 4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-{6-[(3R)-3- 495.0 (dimethylamino)pyrrolidin-1-yl]1H-benzimidazol-2-yl}quinolin- 2(1H)-one 1011 6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 507.1 benzimidazol-2-yl}-4-{[(3S)-1-methylpyrrolidin-3- yl]amino}quinolin-2(1H)-one 1012 6-chloro-3-{6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1H- 521.1 benzimidazol-2-yl}-4-[(1-methylpiperidin-4-yl)amino]quinolin- 2(1H)-one 1013 4-amino-7-(methylamino)-3-[6-(4-methylpiperazin-1-yl)-1H- 404.5 benzimidazol-2-yl]quinolin-2(1H)-one 1014 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(2-morpholin-4-yl-2- 502.0 pyridin-3-ylethyl)amino]quinolin-2(1H)-one 1015 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[2-(dimethylamino)-2- 460.0 pyridin-3-ylethyl]amino}quinolin-2(1H)-one 1016 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-{3- 547.1 [(dimethylamino)methyl]pyrrolidin-1-yl}-1H-benzimidazol-2- yl)quinolin-2(1H)-one 1017 6-chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H- 521.1 benzimidazol-2-yl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one 1018 6-chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H- 507.1 benzimidazol-2-yl)-4-[(3S)-pyrrolidin-3-ylamino]quinolin- 2(1H)-one 1019 4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-(6-{3- 509.1 [(dimethylamino)methyl]pyrrolidin-1-yl}-1H-benzimidazol-2- yl)quinolin-2(1H)-one 1020 chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H- 521.1 benzimidazol-2-yl)-4-{[(3S)-1-methylpyrrolidin-3- yl]amino}quinolin-2(1H)-one 1021 6-chloro-3-(6-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1H- 535.1 benzimidazol-2-yl)-4-[(1-methylpiperidin-4-yl)amino]quinolin- 2(1H)-one 1022 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(3S)-piperidin-3- 408.9 ylmethyl]amino}quinolin-2(1H)-one 1023 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(3R)-piperidin-3- 408.9 ylmethyl]amino}quinolin-2(1H)-one 1024 N-(3-{[4-amino-3-(1H-benzimidazol-2-yl)-2-oxo-1,2- 426.4 dihydroquinolin-5-yl]oxy}phenyl)acetamide 1025 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-{6-[3- 533.1 (dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}quinolin- 2(1H)-one 1026 6-chloro-3-{6-[3-(dimethylamino)pyrrolidin-1-yl]-1H- 507.1 benzimidazol-2-yl}-4-(piperidin-4-ylamino)quinolin-2(1H)-one 1027 4-{[(2R)-2-aminobutyl]amino}-6-chloro-3-{6-[3- 495.0 (dimethylamino)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}quinolin- 2(1H)-one 1028 6-chloro-3-{6-[3-(dimethylamino)pyrrolidin-1-yl]-1H- 521.1 benzimidazol-2-yl}-4-[(1-methylpiperidin-4-yl)amino]quinolin- 2(1H)-one 1029 4-amino-7-[[2-(dimethylamino)ethyl](methyl)amino]-3-[6-(4- 475.6 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 1030 4-amino-5-fluoro-3-[6-(1,4-oxazepan-4-ylcarbonyl)-1H- 422.4 benzimidazol-2-yl]quinolin-2(1H)-one 1031 methyl 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol- 433.5 2-yl]-2-oxo-1,2-dihydroquinoline-6-carboxylate 1032 4-amino-N-benzyl-3-[5-(4-methylpiperazin-1-yl)-1H- 508.6 benzimidazol-2-yl]-2-oxo-1,2-dibydroquinoline-6-carboxamide 1033 4-amino-3-{6-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-1H- 474.6 benzimidazol-2-yl}quinolin-2(1H)-one 1034 4-amino-7-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H- 421.5 benzimidazol-2-yl]quinolin-2(1H)-one 1035 4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-7- 407.5 fluoroquinolin-2(1H)-one 1036 4-amino-3-{6-[(2-aminoethyl)(methyl)amino]-1H-benzimidazol- 349.4 2-yl}quinolin-2(1H)-one 1037 4-amino-3-{6-[[(2-ethyl-4-methyl-1H-imidazol-5- 428.5 yl)methyl](methyl)amino]-1H-benzimidazol-2-yl}quinolin- 2(1H)-one 1038 4-amino-3-[6-(hydroxymethyl)-1H-benzimidazol-2-yl]quinolin- 307.3 2(1H)-one 1039 4-amino-3-(6-{methyl[(2R)-pyrrolidin-2-ylmethyl]amino}-1H- 389.5 benzimidazol-2-yl)quinolin-2(1H)-one 1040 4-amino-3-{6-[(1H-imidazol-2-ylmethyl)(methyl)amino]-1H- 386.4 benzimidazol-2-yl}quinolin-2(1H)-one 1041 4-amino-3-{6-[(2-furylmethyl)(methyl)amino]-1H-benzimidazol- 386.4 2-yl}quinolin-2(1H)-one 1042 4-amino-3-{6-[methyl(piperidin-4-ylmethyl)amino]-1H- 403.5 benzimidazol-2-yl}quinolin-2(1H)-one 1043 4-amino-3-{6-[methyl(piperidin-3-ylmethyl)amino]-1H- 403.5 benzimidazol-2-yl}quinolin-2(1H)-one 1044 4-amino-3-(6-{methyl[2-(methylamino)ethyl]amino}-1H- 363.4 benzimidazol-2-yl)quinolin-2(1H)-one 1045 6-acetyl-4-amino-3-[6-(4-methylpiperazin-1-yl)-1H- 417.5 benzimidazol-2-yl]quinolin-2(1H)-one 1046 4-amino-5-[2-(methylamino)phenoxy]-3-[6-(4-methylpiperazin- 496.6 1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 1047 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2S)-piperidin-2- 408.9 ylmethyl]amino}quinolin-2(1H)-one 1048 4-amino-3-[6-(1,4-oxazepan-4-yl)-1H-benzimidazol-2- 376.4 yl]quinolin-2(1H)-one 1049 4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6- 407.5 fluoroquinolin-2(1H)-one 1050 6-chloro-3-(5-chloro-1H-benzimidazol-2-yl)-4-[(3R)-pyrrolidin- 415.3 3-ylamino]quinolin-2(1H)-one 1051 4-amino-6-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H- 478.5 benzimidazol-2-yl]-7-morpholin-4-ylquinolin-2(1H)-one 1052 4-amino-6-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H- 462.5 benzimidazol-2-yl]-7-pyrrolidin-1-ylquinolin-2(1H)-one 1053 4-amino-7-(dimethylamino)-6-fluoro-3-[5-(4-methylpiperazin-1- 436.5 yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 1054 4-amino-6-fluoro-7-(4-methylpiperazin-1-yl)-3-[5-(4- 491.6 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 1055 4-amino-6-fluoro-7-[(4-methoxybenzyl)amino]-3-[5-(4- 528.6 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 1056 4-amino-6-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H- 499.6 benzimidazol-2-yl]-7-[(pyridin-4-ylmethyl)amino]quinolin- 2(1H)-one 1057 4-amino-7-[[2-(dimethylamino)ethyl](methyl)amino]-6-fluoro-3- 493.6 [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin- 2(1H)-one 1058 4-amino-3-[6-(4-cyclopentylpiperazin-1-yl)-1H-benzimidazol-2- 447.5 yl]-5-fluoroquinolin-2(1H)-one 1059 4-amino-6-[1-(methylamino)ethyl]-3-[6-(4-methylpiperazin-1- 432.5 yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one 1060 4-amino-5-fluoro-3-[6-(1,4-oxazepan-4-yl)-1H-benzimidazol-2- 394.4 yl]quinolin-2(1H)-one 1061 4-amino-3-{6-[methyl(pyridin-3-ylmethyl)amino]-1H- 397.5 benzimidazol-2-yl}quinolin-2(1H)-one 1062 4-amino-3-{6-[({5-[(dimethylamino)methyl]-2- 443.5 furyl}methyl)(methyl)amino]-1H-benzimidazol-2-yl}quinolin- 2(1H)-one 1063 4-amino-3-[6-(4-oxopiperidin-1-yl)-1H-benzimidazol-2- 374.4 yl]quinolin-2(1H)-one 1064 4-amino-3-{6-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-1H- 458.6 benzimidazol-2-yl}quinolin-2(1H)-one 1065 4-amino-3-[6-(4-{[(4-benzylmorpholin-2- 564.7 yl)methyl]amino}piperidin-1-yl)-1H-benzimidazol-2-yl]quinolin- 2(1H)-one 1066 3-(1H-benzimidazol-2-yl)-6-bromo-4-{[2- 427.3 (dimethylamino)ethyl]amino}quinolin-2(1H)-one 1067 4-{[(1R,2R)-2-aminocyclohexyl]amino}-3-(1H-benzimidazol-2- 453.4 yl)-6-bromoquinolin-2(1H)-one 1068 3-(1H-benzimidazol-2-yl)-6-bromo-4-[(piperidin-4- 453.4 ylmethyl)amino]quinolin-2(1H)-one 1069 4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-6- 453.4 bromoquinolin-2(1H)-one 1070 3-(1H-benzimidazol-2-yl)-6-bromo-4-{[2- 413.3 (methylamino)ethyl]amino}quinolin-2(1H)-one 1071 3-(1H-benzimidazol-2-yl)-6-bromo-4-[(3S)-pyrrolidin-3- 425.3 ylamino]quinolin-2(1H)-one 1072 3-(1H-benzimidazol-2-yl)-6-bromo-4-[(3R)-pyrrolidin-3- 425.3 ylamino]quinolin-2(1H)-one 1073 3-(1H-benzimidazol-2-yl)-6-bromo-4-[(piperidin-2- 453.4 ylmethyl)amino]quinolin-2(1H)-one 1074 4-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-[5-(4- 527.6 methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2-oxo-1,2- dihydroquinoline-6-carboxamide 1075 4-amino-N-methyl-3-[5-(4-methylpiperazin-1-yl)-1H- 529.7 benzimidazol-2-yl]-N-(1-methylpiperidin-4-yl)-2-oxo-1,2- dihydroquinoline-6-carboxamide 1076 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-2- 502.6 oxo-N-(tetrahydrofuran-2-ylmethyl)-1,2-dihydroquinoline-6- carboxamide 1077 3-(1H-benzimidazol-2-yl)-6-chloro-4-[(3R)-pyrrolidin-3- 380.8 ylamino]quinolin-2(1H)-one 1078 3-(1H-benzimidazol-2-yl)-6-chloro-4-{[(2R)-piperidin-2- 408.9 ylmethyl]amino}quinolin-2(1H)-one 1079 4-amino-3-{6-[(3R)-3,4-dimethylpiperazin-1-yl]-1H- 407.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 1080 6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-{[2- 435.3 (dimethylamino)ethyl]amino}quinolin-2(1H)-one 1081 4-{[(1R,2R)-2-aminocyclohexyl]amino}-6-chloro-3-(6-chloro-5- 461.3 fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one 1082 6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4- 461.3 [(piperidin-4-ylmethyl)amino]quinolin-2(1H)-one 1083 4-[(4-aminocyclohexyl)amino]-6-chloro-3-(6-chloro-5-fluoro- 461.3 1H-benzimidazol-2-yl)quinolin-2(1H)-one 1084 6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-{[2- 421.3 (methylamino)ethyl]amino}quinolin-2(1H)-one 1085 6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-[(3S)- 433.3 pyrrolidin-3-ylamino]quinolin-2(1H)-one 1086 6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4-[(3R)- 433.3 pyrrolidin-3-ylamino]quinolin-2(1H)-one 1087 6-chloro-3-(6-chloro-5-fluoro-1H-benzimidazol-2-yl)-4- 461.3 [(piperidin-2-ylmethyl)amino]quinolin-2(1H)-one 1088 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-chloro- 473.3 5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one 1089 4-[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]-6-chloro-3-(6-chloro- 473.3 5-fluoro-1H-benzimidazol-2-yl)quinolin-2(1H)-one 1090 4-amino-6-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H- 393.4 benzimidazol-2-yl]quinolin-2(1H)-one 1091 4-amino-3-(1H-benzimidazol-2-yl)-5-(methylamino)quinolin- 306.3 2(1H)-one 1092 4-amino-3-{6-[(2S)-2,4-dimethylpiperazin-1-yl]-1H- 407.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 1093 4-amino-5-fluoro-3-{6-[(2S)-2-methylpiperazin-1-yl]-1H- 393.4 benzimidazol-2-yl}quinolin-2(1H)-one 1094 4-amino-3-{6-[(2S)-4-isopropyl-2-methylpiperazin-1-yl]-1H- 417.5 benzimidazol-2-yl}quinolin-2(1H)-one 1095 4-amino-5,7-difluoro-3-[5-(4-methylpiperazin-1-yl)-1H- 411.4 benzimidazol-2-yl]quinolin-2(1H)-one 1096 3-(1H-benzimidazol-2-yl)-6-bromo-4-{[(2S)-piperidin-2- 453.4 ylmethyl]amino}quinolin-2(1H)-one 1097 3-(1H-benzimidazol-2-yl)-6-bromo-4-{[(2R)-piperidin-2- 453.4 ylmethyl]amino}quinolin-2(1H)-one 1098 4-amino-3-{6-[methyl(1,3-thiazol-2-ylmethyl)amino]-1H- 403.5 benzimidazol-2-yl}quinolin-2(1H)-one 1099 4-amino-3-{6-[(1-ethylpiperidin-4-yl)(methyl)amino]-1H- 417.5 benzimidazol-2-yl}quinolin-2(1H)-one 1100 4-amino-3-[6-(4-morpholin-4-ylpiperidin-1-yl)-1H- 445.5 benzimidazol-2-yl]quinolin-2(1H)-one 1101 4-amino-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2- 432.5 yl]-5-(methylamino)quinolin-2(1H)-one 1102 4-amino-3-{6-[methyl(pyridin-2-ylmethyl)amino]-1H- 397.5 benzimidazol-2-yl}quinolin-2(1H)-one 1103 4-amino-3-{6-[(2S)-2,4-dimethylpiperazin-1-yl]-1H- 389.5 benzimidazol-2-yl}quinolin-2(1H)-one 1104 4-amino-3-{6-[(2S)-2-methylpiperazin-1-yl]-1H-benzimidazol-2- 375.4 yl}quinolin-2(1H)-one 1105 N-[2-(4-amino-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 348.4 benzimidazol-6-yl]-N-methylacetamide 1106 4-amino-5-fluoro-3-{6-[(2S)-4-isopropyl-2-methylpiperazin-1- 435.5 yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one 1107 4-amino-3-{6-[(3R)-3,4-dimethylpiperazin-1-yl]-1H- 389.5 benzimidazol-2-yl}quinolin-2(1H)-one 1108 4-[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1H-benzimidazol- 429.5 2-yl)-6-(dimethylamino)quinolin-2(1H)-one 1109 4-amino-3-{6-[(2S)-4-cyclobutyl-2-methylpiperazin-1-yl]-1H- 429.5 benzimidazol-2-yl}quinolin-2(1H)-one 1110 4-amino-5-fluoro-3-[6-(methylamino)-1H-benzimidazol-2- 324.3 yl]quinolin-2(1H)-one 1111 4-amino-3-(1H-benzimidazol-2-yl)-5-(dimethylamino)quinolin- 320.4 2(1H)-one 1112 4-amino-3-(1H-benzimidazol-2-yl)-5-{[2- 363.4 (dimethylamino)ethyl]amino}quinolin-2(1H)-one 1113 4-amino-5-fluoro-3-(5-piperazin-1-yl-1H-benzimidazol-2- 379.4 yl)quinolin-2(1H)-one 1114 4-amino-3-{5-[[2-(dimethylamino)ethyl](methyl)amino]-1H- 395.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 1115 4-amino-5-fluoro-3-{5-[methyl(piperidin-3-ylmethyl)amino]-1H- 421.5 benzimidazol-2-yl}quinolin-2(1H)-one 1116 4-amino-3-(1H-benzimidazol-2-yl)-5-[[2- 377.5 (dimethylamino)ethyl](methyl)amino]quinolin-2(1H)-one 1117 4-amino-5-fluoro-3-{5-[(2R)-4-isopropyl-2-methylpiperazin-1- 435.5 yl]-1H-benzimidazol-2-yl}quinolin-2(1H)-one 1118 4-amino-3-{5-[(2S)-4-ethyl-2-methylpiperazin-1-yl]-1H- 421.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 1119 4-amino-3-(5-{[(1-ethylpyrrolidin-2-yl)methyl]amino}-1H- 421.5 benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one 1120 4-amino-3-(5-{[2-(dimethylamino)-1-methylethyl]amino}-1H- 395.5 benzimidazol-2-yl)-5-fluoroquinolin-2(1H)-one 1121 4-amino-3-{5-[[2-(dimethylamino)-1- 409.5 methylethyl](methyl)amino]-1H-benzimidazol-2-yl}-5- fluoroquinolin-2(1H)-one 1122 4-amino-3-(1H-benzimidazol-2-yl)-5-(1,2- 335.4 dimethylhydrazino)quinolin-2(1H)-one 1123 4-amino-5-fluoro-3-{6-[4-(2-methoxyethyl)piperazin-1-yl]-1H- 437.5 benzimidazol-2-yl}quinolin-2(1H)-one 1124 4-amino-5-fluoro-3-{6-[methyl(1-methylpiperidin-4-yl)amino]- 421.5 1H-benzimidazol-2-yl}quinolin-2(1H)-one 1125 4-amino-5-fluoro-3-(6-{[3-(4-methylpiperazin-1- 450.5 yl)propyl]amino}-1H-benzimidazol-2-yl)quinolin-2(1H)-one 1126 4-amino-5-fluoro-3-(6-{methyl[3-(4-methylpiperazin-1- 464.6 yl)propyl]amino}-1H-benzimidazol-2-yl)quinolin-2(1H)-one 1127 N-[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 366.4 benzimidazol-6-yl]-N-methylacetamide 1128 4-amino-6-fluoro-3-(5-{[(2R)-2-(pyrrolidin-1- 475.5 ylmethyl)pyrrolidin-1-yl]carbonyl}-1H-benzimidazol-2- yl)quinolin-2(1H)-one 1129 4-amino-3-(1H-benzimidazol-2-yl)-5-(ethylamino)quinolin- 320.4 2(1H)-one 1130 4-amino-3-{5-[(2R)-2,4-dimethylpiperazin-1-yl]-1H- 407.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 1131 4-amino-5-fluoro-3-{5-[(2R)-2-methylpiperazin-1-yl]-1H- 393.4 benzimidazol-2-yl}quinolin-2(1H)-one 1132 4-amino-3-{5-[(2R)-4-cyclobutyl-2-methylpiperazin-1-yl]-1H- 447.5 benzimidazol-2-yl}-5-fluoroquinolin-2(1H)-one 1133 4-amino-5-(dimethylamino)-3-[6-(4-isopropylpiperazin-1-yl)- 446.6 1H-benzimidazol-2-yl]quinolin-2(1H)-one 1134 4-amino-5-{[2-(dimethylamino)ethyl]amino}-3-[6-(4- 489.6 isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)- one 1135 4-amino-5-[[2-(dimethylamino)ethyl](methyl)amino]-3-[6-(4- 503.7 isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)- one 1136 4-amino-5-(ethylamino)-3-[6-(4-isopropylpiperazin-1-yl)-1H- 446.6 benzimidazol-2-yl]quinolin-2(1H)-one 1137 N-[2-(4-amino-2-oxo(3-hydroquinolyl))benzimidazol-6-yl]-2- 391.4 (dimethylamino)-N-methylacetamide 1138 4-amino-5-fluoro-3-[6-(9-isopropyl-1-oxa-4,9- 491.6 diazaspiro[5.5]undec-4-yl)-1H-benzimidazol-2-yl]quinolin- 2(1H)-one 1139 4-amino-7-fluoro-3-[6-fluoro-5-(4-methylpiperazin-1-yl)-1H- 411.4 benzimidazol-2-yl]quinolin-2(1H)-one 1140 4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5- 469.5 methylmorpholin-4-yl}-6-fluoro-1H-benzimidazol-2-yl)-5- fluoroquinolin-2(1H)-one 1141 4-amino-3-(5-{(2S,5S)-2-[(dimethylamino)methyl]-5- 451.5 methylmorpholin-4-yl}-6-fluoro-1H-benzimidazol-2-yl)quinolin- 2(1H)-one 1142 4-amino-5-methyl-3-[5-(4-methylpiperazin-1-yl)-1H- 389.5 benzimidazol-2-yl]quinolin-2(1H)-one 1143 4-amino-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5- 443.4 (trifluoromethyl)quinolin-2(1H)-one 1144 4-amino-5-fluoro-3-[6-(2-isopropyl-5-oxa-2,8- 463.5 diazaspiro[3.5]non-8-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)- one 1145 4-amino-6-fluoro-3-[5-(4-isopropylpiperazin-1-yl)-1H- 421.5 benzimidazol-2-yl]quinolin-2(1H)-one 1146 N-[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 464.5 benzimidazol-6-yl]-N-methyl-2-(4-methylpiperazin-1- yl)acetamide 1147 N-[2-(4-amino-5-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-1H- 451.5 benzimidazol-6-yl]-N-methyl-2-morpholin-4-ylacetamide 1148 N-[2-(4-amino-5-fluoro-2-oxo(3-hydroquinolyl))benzimidazol-6- 492.6 yl]-N-methyl-2-morpholin-4-ylacetamide 1149 4-amino-5-fluoro-3-(6-methyl-1H-benzimidazol-2-yl)quinolin- 309.3 2(1H)-one 1150 4-amino-3-[5-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5- 403.5 methylquinolin-2(1H)-one 1151 4-amino-3-{6-[(4-methylpiperazin-1-yl)methyl]-1H- 389.5 benzimidazol-2-yl}quinolin-2(1H)-one 1152 4-amino-3-[6-(1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]-5- 393.4 fluoroquinolin-2(1H)-one 1153 4-amino-5-fluoro-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H- 407.5 benzimidazol-2-yl]quinolin-2(1H)-one 1154 3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-amino-5- 421.4 fluoroquinolin-2(1H)-one 1155 4-amino-3-[6-(4-ethyl-1,4-diazepan-1-yl)-1H-benzimidazol-2- 421.5 yl]-5-fluoroquinolin-2(1H)-one 1156 4-amino-5-fluoro-3-[6-(4-isopropyl-1,4-diazepan-1-yl)-1H- 435.5 benzimidazol-2-yl]quinolin-2(1H)-one

In yet another embodiment, the compound of Structure I is a compound of Structure II, where Structure II has the following formula:

wherein,

-   A is a group having one of the following Structures:     wherein, -   R^(a) is selected from H or straight or branched chain alkyl groups     having from 1 to 6 carbon atoms.

In some embodiments, where the compound of Structure I is a compound of Structure II, R^(a) is a methyl group, and the compound of Structure II is a compound of Structure IIA

In some specific embodiments, the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.

In some embodiments, where the compound of Structure I is a compound of Structure II, R^(a) is a H, and the compound of Structure II is a compound of Structure IIB

In some embodiments, where the compound of Structure I is a compound of Structure II, R^(a) is a methyl group, and the compound of Structure II is a compound of Structure IIC

The compounds of any of the embodiments may be used to prepare medicaments or pharmaceutical formulations for use in any of the methods of the invention.

Pharmaceutical formulations for use with the invention may include any of the compounds, tautomers, or salts of any of the embodiments described above in combination with a pharmaceutically acceptable carrier such as those described herein.

The instant invention also provides for compositions which may be prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts tautomers thereof, or mixtures thereof with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat or ameliorate disorders related to metastacized tumors. The compositions of the inventions may be used to create formulations for use in any of the methods of the invention. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral administration, by nasal administration, by rectal administration, subcutaneous injection, intravenous injection, intramuscular injections, or intraperitoneal injection. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.

For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, pharmaceutically acceptable salts, tautomers, or mixtures thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

As noted above, suspensions may include oils. Such oil include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

For nasal administration, the pharmaceutical formulations and medicaments may be a spray or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.

Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.

Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference in its entirety for all purposes as if fully set forth herein.

The formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.

The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.

Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.

A therapeutically effective dose may vary depending upon the route of administration and dosage form. The preferred compound or compounds of the instant invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED₅₀ is the dose therapeutically effective in 50% of the population. The LD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.

Pharmaceutical formulations and medicaments according to the invention include the compound of Structure I or the tautomers, salts, or mixtures thereof in combination with a pharmaceutically acceptable carrier. Thus, the compounds of the invention may be used to prepare medicaments and pharmaceutical formulations. Such medicaments and pharmaceutical formulations may be used in any of the methods of treatment described herein.

The compounds and formulations of the present invention are particularly suitable for use in combination therapy. Kinase inhibitors for use as anticancer agents in conjunction with the methods or compositions of the present invention include inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as small molecule quinazolines, for example gefitinib (U.S. Pat. No. 5,457,105, U.S. Pat. No. 5,616,582, and U.S. Pat. No. 5,770,599), ZD-6474 (WO 01/32651), erlotinib (Tarceva®, U.S. Pat. No. 5,747,498 and WO 96/30347), and lapatinib (U.S. Pat. No. 6,727,256 and WO 02/02552). Kinase inhibitors for use as anticancer agents in conjunction with the methods of compositions of the present invention also include inibitors of Vascular Endothelial Growth Factor Receptor (VEGFR) kinase inhibitor such as, but not limited to, SU-11248 (WO 01/60814), SU 5416 (U.S. Pat. No. 5,883,113 and WO 99/61422), SU 6668 (U.S. Pat. No. 5,883,113 and WO 99/61422), CHIR-258 (U.S. Pat. No. 6,605,617 and U.S. Pat. No. 6,774,237), vatalanib or PTK-787 (U.S. Pat. No. 6,258,812), VEGF-Trap (WO 02/57423), B43-Genistein (WO-09606116), fenretinide (retinoic acid p-hydroxyphenylamine) (U.S. Pat. No. 4,323,581), IM-862 (WO 02/62826), bevacizumab or Avastin® (WO 94/10202), KRN-951, 3-[5-(methylsulfonylpiperadine methyl)-indolyl]-quinolone, AG-13736 and AG-13925, pyrrolo[2,1-f][1,2,4]triazines, ZK-304709, Veglin®, VMDA-3601, EG-004, CEP-701 (U.S. Pat. No. 5,621,100), and Cand5 (WO 04/09769).

The compounds of the invention may be used to treat a variety of subjects. Suitable subjects include animals such as mammals and humans. Suitable mammals include, but are not limited to, primates such as, but not limited to lemurs, apes, and monkeys; rodents such as rats, mice, and guinea pigs; rabbits and hares; cows; horses; pigs; goats; sheep; marsupials; and carnivores such as felines, canines, and ursines. In some embodiments, the subject or patient is a human. In other embodiments, the subject or patient is a rodent such as a mouse or a rat. In some embodiments, the subject or patient is an animal other than a human and in some such embodiments, the subject or patient is a mammal other than a human.

Purification and Characterization of Compounds

Compounds of the present invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2690 Separation Module (Milford, Mass.). The analytical columns were Alltima C-18 reversed phase, 4.6×250 mm from Alltech (Deerfield, Ill.). A gradient elution was used, typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over a period of 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburg, Pa.). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 5-95% acetonitrile in water with 0.05% TFA; Flow rate 0.8 mL/minute; Molecular weight range 150-850; Cone Voltage 20 V; Column temperature 40° C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 1-95% acetonitrile in water with 0.05% TFA; Flow rate 0.4 mL/minute; Molecular weight range 150-850; Cone Voltage 50 V; Column temperature 30° C.). All masses are reported as those of the protonated parent ions.

GCMS analysis was performed on a Hewlet Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; Injector volume: 1 μL; Initial column temperature: 50° C.; Final column temperature: 250° C.; Ramp time: 20 minutes; Gas flow rate: 1 mL/minute; Column: 5% Phenyl Methyl Siloxane, Model #HP 190915-443, Dimensions: 30.0 m×25 μm×0.25 μm).

Preparative separations were carried out using either a Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by HPLC using a C-18 reversed phase column. Typical solvents employed for the Flash 40 Biotage system were dichloromethane, methanol, ethyl acetate, hexane and triethyl amine. Typical solvents employed for the reverse phase HPLC were varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.

Synthesis of 4-Amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one

A. Synthesis of 5-(4-Methyl-piperazin-1-yl)-2-nitroaniline

Procedure A

5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1-methyl piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N₂. The flask was placed in an oil bath at 100° C. and heated until the 5-chloro-2-nitroaniline was completely reacted (typically overnight) as determined by HPLC. After HPLC confirmed the disappearance of the 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still warm) into 2500 mL of room temperature water with mechanical stirring. The resulting mixture was stirred until it reached room temperature and then it was filtered. The yellow solid thus obtained was added to 1000 mL of water and stirred for 30 minutes. The resulting mixture was filtered, and the resulting solid was washed with TBME (500 mL, 2×) and then was dried under vacuum for one hour using a rubber dam. The resulting solid was transferred to a drying tray and dried in a vacuum oven at 50° C. to a constant weight to yield 670 g (97.8%) of the title compound as a yellow powder.

Procedure B

5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-neck 5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N₂. 1-Methylpiperazine (758.1 g, 840 mL, 7.57 mol) and 200 proof ethanol (508 mL) were added to the reaction flask with stirring. The flask was again purged with N₂, and the reaction was maintained under N₂. The flask was heated in a heating mantle to an internal temperature of 97° C. (+/−5° C.) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 20° C. to 25° C. with stirring, and the reaction was stirred for 2 to 3 hours. Seed crystals (0.20 g, 0.85 mmol) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline were added to the reaction mixture unless precipitation had already occurred. Water (2,450 mL) was added to the stirred reaction mixture over a period of about one hour while the internal temperature was maintained at a temperature ranging from about 20° C. to 30° C. After the addition of water was complete, the resulting mixture was stirred for about one hour at a temperature of 20° C. to 30° C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (3×2.56 L). The golden yellow solid product was dried to a constant weight of 416 g (98.6% yield) under vacuum at about 50° C. in a vacuum oven.

Procedure C

5-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck 12 L round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N₂. 1-Methylpiperazine (977 g, 1.08 L, 9.75 mol) and 100% ethanol (650 mL) were added to the reaction flask with stirring. The flask was again purged with N₂, and the reaction was maintained under N₂. The flask was heated in a heating mantle to an internal temperature of 97° C. (+/−5° C.) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 80° C. with stirring, and water (3.15 L) was added to the mixture via an addition funnel over the period of 1 hour while the internal temperature was maintained at 82° C. (+/−3° C.). After water addition was complete, heating was discontinued and the reaction mixture was allowed to cool over a period of no less than 4 hours to an internal temperature of 20-25° C. The reaction mixture was then stirred for an additional hour at an internal temperature of 20-30° C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (1×1 L), 50% ethanol (1×1 L), and 95% ethanol (1×1 L). The golden yellow solid product was placed in a drying pan and dried to a constant weight of 546 g (99% yield) under vacuum at about 50° C. in a vacuum oven.

B. Synthesis of [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester

Procedure A

A 5000 mL, 4-neck flask was fitted with a stirrer, thermometer, condenser, and gas inlet/outlet. The equipped flask was charged with 265.7 g (1.12 mol. 1.0 eq) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline and 2125 mL of 200 proof EtOH. The resulting solution was purged with N₂ for 15 minutes. Next, 20.0 g of 5% Pd/C (50% H₂O w/w) was added. The reaction was vigorously stirred at 40-50° C. (internal temperature) while H₂ was bubbled through the mixture. The reaction was monitored hourly for the disappearance of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline by HPLC. The typical reaction time was 6 hours.

After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N₂ for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50° C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2×250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H₂O (2×400 mL) and dried at 50° C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.

Procedure B

A 5000 mL, 4-neck jacketed flask was fitted with a mechanical stirrer, condenser, temperature probe, gas inlet, and oil bubbler. The equipped flask was charged with 300 g (1.27 mol) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline and 2400 mL of 200 proof EtOH (the reaction may be and has been conducted with 95% ethanol and it is not necessary to use 200 proof ethanol for this reaction). The resulting solution was stirred and purged with N₂ for 15 minutes. Next, 22.7 g of 5% Pd/C (50% H₂O w/w) was added to the reaction flask. The reaction vessel was purged with N₂ for 15 minutes. After purging with N₂, the reaction vessel was purged with H₂ by maintaining a slow, but constant flow of H₂ through the flask. The reaction was stirred at 45-55° C. (internal temperature) while H₂ was bubbled through the mixture until the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline was completely consumed as determined by HPLC. The typical reaction time was 6 hours.

After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N₂ for 15 minutes. The diamine intermediate is air sensitive so care was taken to avoid exposure to air. 500 g (2.56 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added to the reaction mixture over a period of about 30 minutes. The reaction was stirred at 45-55° C. (internal temperature) under N₂ until the diamine was completely consumed as determined by HPLC. The typical reaction time was about 2 hours. After the reaction was complete, the reaction was filtered while warm through a pad of Celite. The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL). The filtrates were combined in a 5000 mL flask, and about 3300 mL of ethanol was removed under vacuum producing an orange oil. Water (530 mL) and then 1M HCL (350 mL) were added to the resulting oil, and the resulting mixture was stirred. The resulting solution was vigorously stirred while 30% NaOH (200 mL) was added over a period of about 20 minutes maintaining the internal temperature at about 25-30° C. while the pH was brought to between 9 and 10. The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C. The resulting mixture was filtered, and the filter cake was washed with H₂O (3×300 mL). The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven providing 345.9 g (90.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. In an alternative work up procedure, the filtrates were combined and the ethanol was removed under vacuum until at least about 90% had been removed. Water at a neutral pH was then added to the resulting oil, and the solution was cooled to about 0° C. An aqueous 20% NaOH solution was then added slowly with rapid stirring to bring the pH up to 9.2 (read with pH meter). The resulting mixture was then filtered and dried as described above. The alternative work up procedure provided the light tan to light yellow product in yields as high as 97%.

Method for Reducing Water Content of [6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester

[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (120.7 grams) that had been previously worked up and dried to a water content of about 8-9% H₂O was placed in a 2000 mL round bottom flask and dissolved in absolute ethanol (500 mL). The amber solution was concentrated to a thick oil using a rotary evaporator with heating until all solvent was removed. The procedure was repeated two more times. The thick oil thus obtained was left in the flask and placed in a vacuum oven heated at 50° C. overnight. Karl Fisher analysis results indicated a water content of 5.25%. The lowered water content obtained by this method provided increased yields in the procedure of the following Example. Other solvents such as toluene and THF may be used in place of the ethanol for this drying process.

C. Synthesis of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one

Procedure A

[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 mL) in a 5000 mL flask fitted with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the internal temperature was raised to 40° C. When all the solids had dissolved and the solution temperature had reached 40° C., solid KHMDS (376.2 g, 1890 mmol) was added over a period of 5 minutes. When addition of the potassium base was complete, a heterogeneous yellow solution was obtained, and the internal temperature had risen to 62° C. After a period of 60 minutes, the internal temperature decreased back to 40° C., and the reaction was determined to be complete by HPLC (no starting material or uncyclized intermediate was present). The thick reaction mixture was then quenched by pouring it into H₂O (6000 mL) and stirring the resulting mixture until it had reached room temperature. The mixture was then filtered, and the filter pad was washed with water (1000 mL 2×). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50° C. overnight providing 155.3 g (47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.

Procedure B

A 5000 mL 4-neck jacketed flask was equipped with a distillation apparatus, a temperature probe, a N₂ gas inlet, an addition funnel, and a mechanical stirrer. [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (173.0 g, 570 mmol) was charged into the reactor, and the reactor was purged with N₂ for 15 minutes. Dry THF (2600 mL) was then charged into the flask with stirring. After all the solid had dissolved, solvent was removed by distillation (vacuum or atmospheric (the higher temperature helps to remove the water) using heat as necessary. After 1000 mL of solvent had been removed, distillation was stopped and the reaction was purged with N₂. 1000 mL of dry THF was then added to the reaction vessel, and when all solid was dissolved, distillation (vacuum or atmospheric) was again conducted until another 1000 mL of solvent had been removed. This process of adding dry THF and solvent removal was repeated at least 4 times (on the 4^(th) distillation, 60% of the solvent is removed instead of just 40% as in the first 3 distillations) after which a 1 mL sample was removed for Karl Fischer analysis to determine water content. If the analysis showed that the sample contained less than 0.20% water, then reaction was continued as described in the next paragraph. However, if the analysis showed more than 0.20% water, then the drying process described above was continued until a water content of less than 0.20% was achieved.

After a water content of less than or about 0.20% was achieved using the procedure described in the previous paragraph, the distillation apparatus was replaced with a reflux condenser, and the reaction was charged with 2-amino-6-fluoro-benzonitrile (66.2 g, 470 mmol) (in some procedures 0.95 equivalents is used). The reaction was then heated to an internal temperature of 38-42° C. When the internal temperature had reached 38-42° C., KHMDS solution (1313 g, 1.32 mol, 20% KHMDS in THF) was added to the reaction via the additional funnel over a period of 5 minutes maintaining the internal temperature at about 38-50° C. during the addition. When addition of the potassium base was complete, the reaction was stirred for 3.5 to 4.5 hours (in some examples it was stirred for 30 to 60 minutes and the reaction may be complete within that time) while maintaining the internal temperature at from 38-42° C. A sample of the reaction was then removed and analyzed by HPLC. If the reaction was not complete, additional KHMDS solution was added to the flask over a period of 5 minutes and the reaction was stirred at 38-42° C. for 45-60 minutes (the amount of KHMDS solution added was determined by the following: If the IPC ratio is <3.50, then 125 mL was added; if 10.0≧IPC ratio≧3.50, then 56 mL was added; if 20.0≧IPC ratio≧10, then 30 mL was added. The IPC ratio is equal to the area corresponding to 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one) divided by the area corresponding to the uncyclized intermediate). Once the reaction was complete (IPC ratio>20), the reactor was cooled to an internal temperature of 25-30° C., and water (350 mL) was charged into the reactor over a period of 15 minutes while maintaining the internal temperature at 25-35° C. (in one alternative, the reaction is conducted at 40° C. and water is added within 5 minutes. The quicker quench reduces the amount of impurity that forms over time). The reflux condenser was then replaced with a distillation apparatus and solvent was removed by distillation (vacuum or atmospheric) using heat as required. After 1500 mL of solvent had been removed, distillation was discontinued and the reaction was purged with N₂. Water (1660 mL) was then added to the reaction flask while maintaining the internal temperature at 20-30° C. The reaction mixture was then stirred at 20-30° C. for 30 minutes before cooling it to an internal temperature of 5-10° C. and then stirring for 1 hour. The resulting suspension was filtered, and the flask and filter cake were washed with water (3×650 mL). The solid thus obtained was dried to a constant weight under vacuum at 50° C. in a vacuum oven to provide 103.9 g (42.6% yield) of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one as a yellow powder.

[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (608 g, 2.01 mol) (dried) and 2-amino-6-fluoro-benzonitrile (274 g, 2.01 mol) were charged into a 4-neck 12 L flask seated on a heating mantle and fitted with a condenser, mechanical stirrer, gas inlet, and temperature probe. The reaction vessel was purged with N₂, and toluene (7.7 L) was charged into the reaction mixture while it was stirred. The reaction vessel was again purged with N₂ and maintained under N₂. The internal temperature of the mixture was raised until a temperature of 63° C. (+/−3° C.) was achieved. The internal temperature of the mixture was maintained at 63° C. (+/−3° C.) while approximately 2.6 L of toluene was distilled from the flask under reduced pressure (380+/−10 torr, distilling head t=40° C. (+/−10° C.) (Karl Fischer analysis was used to check the water content in the mixture. If the water content was greater than 0.03%, then another 2.6 L of toluene was added and distillation was repeated. This process was repeated until a water content of less than 0.03% was achieved). After a water content of less than 0.03% was reached, heating was discontinued, and the reaction was cooled under N₂ to an internal temperature of 17-19° C. Potassium t-butoxide in THF (20% in THF; 3.39 kg, 6.04 moles potassium t-butoxide) was then added to the reaction under N₂ at a rate such that the internal temperature of the reaction was kept below 20° C. After addition of the potassium t-butoxide was complete, the reaction was stirred at an internal temperature of less than 20° C. for 30 minutes. The temperature was then raised to 25° C., and the reaction was stirred for at least 1 hour. The temperature was then raised to 30° C., and the reaction was stirred for at least 30 minutes. The reaction was then monitored for completion using HPLC to check for consumption of the starting materials (typically in 2-3 hours, both starting materials were consumed (less than 0.5% by area % HPLC)). If the reaction was not complete after 2 hours, another 0.05 equivalents of potassium t-butoxide was added at a time, and the process was completed until HPLC showed that the reaction was complete. After the reaction was complete, 650 mL of water was added to the stirred reaction mixture. The reaction was then warmed to an internal temperature of 50° C. and the THF was distilled away (about 3 L by volume) under reduced pressure from the reaction mixture. Water (2.6 L) was then added dropwise to the reaction mixture using an addition funnel. The mixture was then cooled to room temperature and stirred for at least 1 hour. The mixture was then filtered, and the filter cake was washed with water (1.2 L), with 70% ethanol (1.2 L), and with 95% ethanol (1.2 L). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50° C. until a constant weight was obtained providing 674 g (85.4%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.

Purification of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one

A 3000 mL 4-neck flask equipped with a condenser, temperature probe, N₂ gas inlet, and mechanical stirrer was placed in a heating mantle. The flask was then charged with 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (101.0 g, 0.26 mol), and the yellow solid was suspended in 95% ethanol (1000 mL) and stirred. In some cases an 8:1 solvent ratio is used. The suspension was then heated to a gentle reflux (temperature of about 76° C.) with stirring over a period of about 1 hour. The reaction was then stirred for 45-75 minutes while refluxed. At this point, the heat was removed from the flask and the suspension was allowed to cool to a temperature of 25-30° C. The suspension was then filtered, and the filter pad was washed with water (2×500 mL). The yellow solid was then placed in a drying tray and dried in a vacuum oven at 50° C. until a constant weight was obtained (typically 16 hours) to obtain 97.2 g (96.2%) of the purified product as a yellow powder.

D. Preparation of Lactic Acid Salt of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one

A 3000 mL 4-necked jacketed flask was fitted with a condenser, a temperature probe, a N₂ gas inlet, and a mechanical stirrer. The reaction vessel was purged with N₂ for at least 15 minutes and then charged with 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (484 g, 1.23 mol). A solution of D,L-Lactic acid (243.3 g, 1.72 mol of monomer-see the following paragraph), water (339 mL), and ethanol (1211 mL) was prepared and then charged to the reaction flask. Stirring was initiated at a medium rate, and the reaction was heated to an internal temperature of 68-72° C. The internal temperature of the reaction was maintained at 68-72° C. for 15-45 minutes and then heating was discontinued. The resulting mixture was filtered through a 10-20 micron frit collecting the filtrate in a 12 L flask. The 12 L flask was equipped with an internal temperature probe, a reflux condenser, an addition funnel, a gas inlet an outlet, and an overhead stirrer. The filtrate was then stirred at a medium rate and heated to reflux (internal temperature of about 78° C.). While maintaining a gentle reflux, ethanol (3,596 mL) was charged to the flask over a period of about 20 minutes. The reaction flask was then cooled to an internal temperature ranging from about 64-70° C. within 15-25 minutes and this temperature was maintained for a period of about 30 minutes. The reactor was inspected for crystals. If no crystals were present, then crystals of the lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (484 mg, 0.1 mole %) were added to the flask, and the reaction was stirred at 64-70° C. for 30 minutes before again inspecting the flask for crystals. Once crystals were present, stirring was reduced to a low rate and the reaction was stirred at 64-70° C. for an additional 90 minutes. The reaction was then cooled to about 0° C. over a period of about 2 hours, and the resulting mixture was filtered through a 25-50 micron fritted filter. The reactor was washed with ethanol (484 mL) and stirred until the internal temperature was about 0° C. The cold ethanol was used to wash the filter cake, and this procedure was repeated 2 more times. The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven yielding 510.7 g (85.7%) of the crystalline yellow lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one. A rubber dam or inert conditions were typically used during the filtration process. While the dry solid did not appear to be very hygroscopic, the wet filter cake tends to pick up water and become sticky. Precautions were taken to avoid prolonged exposure of the wet filter cake to the atmosphere.

Commercial lactic acid generally contains about 8-12% w/w water, and contains dimers and trimers in addition to the monomeric lactic acid. The mole ratio of lactic acid dimer to monomer is generally about 1.0:4.7. Commercial grade lactic acid may be used in the process described in the preceding paragraph as the monolactate salt preferentially precipitates from the reaction mixture.

Identification of Metabolites

Two metabolites of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (Compound 1) have been identified and characterized in pooled rat plasma from a 2 week toxicology study as described in the references incorporated herein. The two identified metabolites were the piperazine N-oxide compound (Compound 2) and the N-demethylated compound (Compound 3) shown below.

IC₅₀s of Compounds 1-3

The kinase activity of a number of protein tyrosine kinases was measured using the procedures described in the various references incorporated herein. Some of these are shown in the following Table.

Table. IC₅₀s of Compounds 1-3 IC₅₀ (μM) VEGFR VEGFR Compound flt flk1 bFGFR PDGFR Flt3 c-kit Compound 1 0.010 0.013 0.008 0.027 0.0001 0.0015 Compound 2 0.004 0.009 0.005 0.010 0.0004 0.0002 Compound 3 0.019 0.012 0.019 0.037 0.0001 0.0002

Synthesis of 4-Amino-5-fluoro-3-[6-(4-methyl-4-oxidopiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 2) and 4-Amino-5-fluoro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)quinolin-2(1H)-one (Compound 3)

To confirm the structures of the identified metabolites of Compound 1, the metabolites were independently synthesized.

Compound 2, the N-oxide metabolite of Compound 1, was synthesized as shown in the scheme below. Compound 1 was heated in a mixture of ethanol, dimethylacetamide and hydrogen peroxide. Upon completion of the reaction, Compound 2 was isolated by filtration and washed with ethanol. If necessary, the product could be further purified by column chromatography.

Compound 3, the N-desmethyl metabolite of Compound 1, was synthesized as shown in the scheme below. 5-Chloro-2-nitroaniline was treated with piperazine to yield 4 which was subsequently protected with a butyloxycarbonyl (Boc) group to yield 5. Reduction of the nitro group followed by condensation with 3-ethoxy-3-iminopropionic acid ethyl ester gave 6. Condensation of 6 with 6-fluoroanthranilonitrile using potassium hexamethyldisilazide as the base yielded 7. Crude 7 was treated with aqueous HCl to yield the desired metabolite as a yellow/brown solid after purification.

To identify plasma biomarkers of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one treatment, the 4T 1 spontaneously metastatic mouse breast tumor model was used, and circulating serum markers were analyzed by ELISA.

4T1 breast tumor cells were grown as subcutaneous tumors in BALB/C mice, and treatment (10, 30, 60, 100, and 150 mg/kg) with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1) were initiated when tumors were approximately 150 mm³. Mice were dosed orally, daily for 18 days.

The serum was collected from individual animals after 18 days, and the levels of circulating cell adhesion molecules, soluble ICAM, VCAM, and E-selectin, were measured by ELISA assay.

FIG. 1 is a graph showing the effects of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one in the 4T1 murine breast tumor model. The growth of subcutaneous tumors was inhibited (40-80% compared to control), liver metastases were completely inhibited, and lung metastases were inhibited by 60-97% after 18 days of dosing. Various data regarding the incidence of metastases is shown in FIG. 1 and included in the following Table % Inhi- # of Liver bition P values Liver Metastases Incidence of Metastases vs. vs. Treatment Group (n) Metastases Mean +/− SD Vehicle Vehicle Vehicle (water) (9) 8/9 17.9 +/− 15.4 n/a n/a  10 mpk (8) 7/8 22.0 +/− 32.3 0 0.810  30 mpk (10)  6/10 3.1 +/− 3.5 83 0.014  60 mpk (10)  5/10 0.7 +/− 0.9 94 0.002 100 mpk (10)  1/10  4.1 +/− 13.0 77 0.010 150 mpk (9) 0/9 0.0 +/− 0.0 100 0.002

Wells of a Nunc Maxisorb “U” bottom microtiter plate (#449824) were coated with monoclonal capture antibody, rat anti-mouse VCAM-1 (R&D Systems #BCA12), at 5 μg/mL in phosphate buffered saline (PBS), 50 μL/well, and incubated at 37° C. for 1 hour. The plates were washed 3 times with wash buffer [PBS containing 0.1% Tween 20 and 1% goat serum (Gibco BRL #16210-072)]. Wells were blocked with 150 μL/well wash buffer and incubated at 37° C. for 1 hour. The blocking solution was removed from the wells and the standard (recombinant mouse VCAM-1/Fc Chimera NOS derived R&D Systems #643-VM) and samples were diluted in wash buffer and added to the wells.

The standard was used at a range of 4000 pg/mL to 31 pg/mL. The serum samples were diluted 1/200 followed by 3-fold serial dilutions. The samples and standards were added at 50 μL/well and incubated at 37° C. for 1 hour. The plates were washed three times and incubated at 37° C. for 1 hour with the primary antibody (biotinylated goat anti-mouse VCAM-1, R&D Systems #BAF643) diluted 1/200 in wash buffer, 50 μL/well. The plates were washed as described above and incubated at 37° C. for 1 hour with stepavidin-HRP (R&D Systems #DY998) 1/200 in PBS/1% goat serum without Tween 20.

The plates were washed three times with wash buffer and three times with PBS. They were then developed with TMB substrate (Kirkegaard & Perry labs # 50-76-00) 50 μL/well and incubated at room temperature for 10 minutes. The reaction was stopped with the addition of 50 μL/well 4N H₂SO₄, and the plates were read at 450-550 dual wavelength on the Molecular Devices Vmax plate reader.

Wells of a Nunc Maxisorb “U” bottom microtiter plate (#449824) were coated with monoclonal capture antibody, rat anti-mouse ICAM-1 (R&D Systems #BSA2), at 5 μg/mL in phosphate buffered saline (PBS), 50 μL/well and incubated at 37° C. for 1 hour. The plates were washed 3 times with wash buffer [PBS containing 0.1% Tween 20 and 1% Carnation Nonfat Dry Milk]. Wells were blocked with 150 μL/well wash buffer and incubated at 37° C. for 1 hour. The blocking solution was removed from the wells and the standard (a pool of serum from mice implanted with KM12L4a or 4T1 tumors) and samples were diluted in wash buffer and added to the wells.

The standard was used at a dilution range of 1/10-1/1280. The serum samples were diluted 1/15 followed by 3-fold serial dilutions. The samples and standards were added at 50 μL/well and incubated at 37° C. for 1 hour. The plates were washed three times and incubated at 37° C. for 1 hour with the primary antibody (goat anti-ICAM-1, Santa Cruz Biotechnology #sc-1511) diluted 1/250 in wash buffer, 50 μL/well. The plates were washed as above and incubated at 37° C. for 1 hour with 50 μL/well of the secondary antibody (swine anti-goat IgG HRPO labeled, Caltag #G50007) 1/2000 in wash buffer.

The plates were washed three times with wash buffer and three times with PBS, then developed with TMB substrate (Kirkegaard & Perry labs # 50-76-00) 50 μL/well and incubated at room temperature for 10 minutes. The reaction was stopped with the addition of 50 μL/well 4N H₂SO₄, and the plates were read at 450-550 dual wavelength on the Molecular Devices Vmax plate reader.

Serum samples were assayed by the R&D Systems Quantikine M, Mouse sE-Selectin Immunoassay kit #MESOO according to the manufacturer's protocol.

In Vivo KM12L4a Human Colon Xenografts

Female Nu/nu mice (6-8 weeks old, 18-22 grams) were obtained from Charles River Laboratories (Wilmington, Mass.). Tumor cells (2×10⁶ KM12L4a) were implanted subcutaneous into the flank of mice and allowed to grow to the desired size before treatment was initiated. Tumor bearing mice were administered with 100 mg/kg of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one for 7 days, and individual mice were euthanized. The tumors were resected and flash frozen in liquid nitrogen.

Zymography for MMP-2 and MMP-9 Activity

Resected tumors were lysed in RIPA buffer (1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% Sodium dodecylsulphate in 1× phosphate buffered saline, pH 7.2) containing protease inhibitors (Roche Molecular Biochemicals) and phosphatase inhibitors (Sigma). 50 μg of total proteins were analyzed by gelatin zymography on 12% SDS polyacrylamide with gelatin substrate. After electrophoresis, gels were washed twice for 15 minutes in 2.5% Triton X-100, incubated overnight at 37° C. in 50 mM Tris-HCl and 10 mM CaCl₂, pH 7.6, and stained with 0.5% Comassie Blue and destained with 50% methanol.

ELISA

VEGF-A protein levels in KM12L4a tumor lysates were quantified using a commercially available ELISA kit (R and D Systems, Minneapolis, Minn.) according to the manufacturer's procedures.

Analysis of KM12L4a human colon tumors, removed after in vivo administration of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one, showed reduced VEGF production and decreased MMP-9 activity. These changes were accompanied by decreased tumor cell proliferation (Ki67), induced apoptosis (increased PARP cleavage and caspase-3) and reduced vascular density (CD31) as seen by antibody immunohistochemistry staining.

The preparation of numerous quinolinone benzimidazole compounds useful in inhibiting angiogenesis and vascular endothelial growth factor receptor tyrosine kinases and in inhibiting other tyrosine and serine/threonine kinases including 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one or a tautomer thereof is disclosed in the following documents which are each hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein: U.S. Pat. No. 6,605,617; U.S. Pat. No. 6,756,383; U.S. patent application Ser. No. 10/116,117 filed (published on Feb. 6, 2003, as U.S. 2003/0028018 A1); U.S. patent application Ser. No. 10/644,055 (published on May 13, 2004, U.S. Patent Application No. 2004/0092535); U.S. patent application Ser. No. 10/983,174; U.S. patent application Ser. No. 10/706,328 (published on Nov. 4, 2004, as 2004/0220196); U.S. patent application Ser. No. 10/982,757; and U.S. patent application Ser. No. 10/982,543.

Western Blot Analysis

HUVECs were cultured in EGM (Endothelial Cell Growth Media) with or without 100 nM 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one (Compound 1), and cell lysates were collected at 0, 16, and 24 hours post-treatment. Equal amounts of proteins were loaded in 4-20% SDS-PAGE, and the gels were probed with antibodies against ICAM, VCAM, α5 integrin, and αv integrin. The equal loading and efficiency was evaluated by probing with anti β-actin antibody. The expression of ICAM, VCAM, and α5 integrin was decreased with 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one treatment in HUVECs in vitro.

It should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms at a time, it should be understood that the invention encompasses any tautomeric form of the drawn structure. For example, the compound of Structure IIIB is shown below with one tautomer, Tautomer IIIBa:

Other tautomers of the compound of Structure IIIB, Tautomer IIIBb and Tautomer IIIBc, are shown below:

All documents or references cited herein are hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein.

It is understood that the invention is not limited to the embodiments set forth herein for illustration, but embraces all such forms thereof as come within the scope of the invention. 

1. A method of modulating an inflammatory response and/or reducing cellular adhesion in a subject, comprising: administering to the subject a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, wherein the inflammatory response is modulated in the subject and/or cellular adhesion is reduced in the subject after administration, and Structure I has the following formula:

wherein, R¹, R², R³, and R⁴ may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —CN, —NO₂, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷ groups, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and —C(═O)R¹⁸ groups; R⁵, R⁶, R⁷, and R⁸ may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —NO₂, —OH, —OR¹⁹ groups, —NR²⁰R²¹ groups, —SH, —SR²² groups, —S(═O)R²³ groups, —S(═O)₂R²⁴ groups, —CN, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)R²⁵ groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹² is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups; R¹³ is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl)(aryl)amino groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁵ and R¹⁹ may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl, substituted and unsubstituted diheterocyclylaminoalkyl, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁶ and R²⁰ may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups; R¹⁷ and R²¹ may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁸, R²³, R²⁴, and R²⁵ may be the same or different and are independently selected from the group consisting of H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, —OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and —N(aryl)O-aryl groups; and R²² is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.
 2. The method of claim 1, wherein the levels of circulating adhesion molecules are reduced in the subject after administration.
 3. The method of claim 1, wherein the amount of at least one of inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule is reduced in the subject after administration.
 4. The method of claim 1, further comprising: measuring the amount of at least one of inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule in the subject after administration of the compound, the tautomer, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
 5. The method of claim 1, wherein the amount of a matrix metalloprotease is reduced in the subject after administration.
 6. The method of claim 5, wherein the matrix metalloprotease is matrix metalloprotease-2 or matrix metalloprotease-9.
 7. The method of claim 1, wherein the compound of Structure I is a compound of Structure II, and Structure II has the following formula:

wherein, A is a group having one of the following Structures:

wherein, R^(a) is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms.
 8. The method of claim 7, wherein R^(a) is a methyl group, and the compound of Structure II has the Structure IIA having the following formula:


9. The method of claim 8, wherein the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.
 10. The method of claim 7, wherein R^(a) is a hydrogen, and the compound of Structure II has the Structure IIB having the following formula:


11. The method of claim 7, wherein R^(a) is a methyl group, and the compound of Structure II has the Structure IIC having the following formula:


12. The method of claim 1, wherein the pharmaceutically acceptable salt of the compound of Structure I, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.
 13. The method of claim 1, wherein the subject is a cancer patient.
 14. The method of claim 1, wherein R¹² and R¹³ are both H.
 15. The method of claim 1, wherein at least one of R⁶ or R⁷ is a substituted or unsubstituted heterocyclyl group.
 16. The method of claim 1, wherein at least one of R⁶ or R⁷ is a substituted or unsubstituted piperazine group.
 17. The method of claim 1, wherein R¹ is F and R², R³, R⁴, R⁵, and R⁸ are each H and one of R⁶ or R⁷ is H.
 18. A method of identifying a subject in need of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof, comprising measuring the amount of at least one cell adhesion molecule in the subject before, during, or after administration of the compound of Structure I, the tautomer of the compound, the pharmaceutically acceptable salt of the compound, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof to the subject, wherein the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule, and Structure I has the following formula:

wherein, R¹, R², R³, and R⁴ may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —CN, —NO₂, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷ groups, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and —C(═O)R¹⁸ groups; R⁵, R⁶, R⁷, and R⁸ may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —NO₂, —OH, —OR¹⁹ groups, —NR²⁰R²¹ groups, —SH, —SR²² groups, —S(═O)R²³ groups, —S(═O)₂R²⁴ groups, —CN, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)R²⁵ groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹² is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups; R¹³ is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl)(aryl)amino groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁵ and R¹⁹ may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl, substituted and unsubstituted diheterocyclylaminoalkyl, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁶ and R²⁰ may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups; R¹⁷ and R²¹ may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁸, R²³, R²⁴, and R²⁵ may be the same or different and are independently selected from the group consisting of H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, —OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and —N(aryl)O-aryl groups; and R²² is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.
 19. The method of claim 18, wherein the compound of Structure I is a compound of Structure II, and Structure II has the following formula:

wherein, A is a group having one of the following Structures:

wherein, R^(a) is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms.
 20. The method of claim 19, wherein R^(a) is a methyl group, and the compound of Structure II has the Structure IIA having the following formula:


21. The method of claim 20, wherein the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.
 22. The method of claim 19, wherein R^(a) is a hydrogen, and the compound of Structure II has the Structure IIB having the following formula:


23. The method of claim 19, wherein R^(a) is a methyl group, and the compound of Structure II has the Structure IIC having the following formula:


24. The method of claim 18, wherein the pharmaceutically acceptable salt of the compound of Structure I, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.
 25. The method of claim 18, wherein the patient is a cancer patient.
 26. The method of claim 18, wherein R¹² and R¹³ are both H.
 27. The method of claim 18, wherein at least one of R⁶ or R⁷ is a substituted or unsubstituted heterocyclyl group.
 28. The method of claim 18, wherein at least one of R⁶ or R⁷ is a substituted or unsubstituted piperazine group.
 29. The method of claim 18, wherein R¹ is F and R², R³, R⁴, R⁵, and R⁸ are each H and one of R⁶ or R⁷ is H.
 30. The method of claim 18, further comprising withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample.
 31. A method of monitoring the progression of a disease or treatment in a subject, comprising: measuring the amount of at least one cell adhesion molecule in the subject after administration of a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt of the tautomer, or a mixture thereof to the subject, wherein the cell adhesion molecule is selected from inducible cell adhesion molecule, vascular cell adhesion molecule, or endothelial leukocyte adhesion molecule, and Structure I has the following formula:

wherein, R¹, R², R³, and R⁴ may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —CN, —NO₂, —OH, —OR¹⁵ groups, —NR¹⁶R¹⁷ groups, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, and —C(═O)R¹⁸ groups; R⁵, R⁶, R⁷, and R⁸ may be the same or different and are independently selected from the group consisting of H, Cl, Br, F, I, —NO₂, —OH, —OR¹⁹ groups, —NR²⁰R²¹ groups, —SH, —SR²² groups, —S(═O)R²³ groups, —S(═O)₂R²⁴ groups, —CN, substituted and unsubstituted amidinyl groups, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted primary, secondary, and tertiary alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)R²⁵ groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹² is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups; R¹³ is selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —OH, alkoxy groups, aryloxy groups, —NH₂, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted arylamino groups, substituted and unsubstituted dialkylamino groups, substituted and unsubstituted diarylamino groups, substituted and unsubstituted (alkyl)(aryl)amino groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁵ and R¹⁹ may be the same or different and are independently selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted heterocyclylalkyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl, substituted and unsubstituted diheterocyclylaminoalkyl, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁶ and R²⁰ may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups; R¹⁷ and R²¹ may be the same or different and are independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heterocyclyl groups, —C(═O)H, —C(═O)-alkyl groups, —C(═O)-aryl groups, —C(═O)NH₂, —C(═O)NH(alkyl) groups, —C(═O)NH(aryl) groups, —C(═O)N(alkyl)₂ groups, —C(═O)N(aryl)₂ groups, —C(═O)N(alkyl)(aryl) groups, —C(═O)O-alkyl groups, —C(═O)O-aryl groups, substituted and unsubstituted heterocyclylalkyl groups, substituted and unsubstituted aminoalkyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted dialkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted diarylaminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, —C(═O)-heterocyclyl groups, —C(═O)—O-heterocyclyl groups, —C(═O)NH(heterocyclyl) groups, —C(═O)—N(heterocyclyl)₂ groups, —C(═O)—N(alkyl)(heterocyclyl) groups, —C(═O)—N(aryl)(heterocyclyl) groups, substituted and unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted hydroxyalkyl groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted aryloxyalkyl groups, and substituted and unsubstituted heterocyclyloxyalkyl groups; R¹⁸, R²³, R²⁴, and R²⁵ may be the same or different and are independently selected from the group consisting of H, —NH₂, —NH(alkyl) groups, —NH(aryl) groups, —N(alkyl)₂ groups, —N(aryl)₂ groups, —N(alkyl)(aryl) groups, —NH(heterocyclyl) groups, —N(heterocyclyl)(alkyl) groups, —N(heterocyclyl)(aryl) groups, —N(heterocyclyl)₂ groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, —OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyl groups, —NHOH, —N(alkyl)OH groups, —N(aryl)OH groups, —N(alkyl)O-alkyl groups, —N(aryl)O-alkyl groups, —N(alkyl)O-aryl groups, and —N(aryl)O-aryl groups; and R²² is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.
 32. The method of claim 31, wherein the compound of Structure I is a compound of Structure II, and Structure II has the following formula:

wherein, A is a group having one of the following Structures:

wherein, R^(a) is selected from H or straight or branched chain alkyl groups having from 1 to 6 carbon atoms.
 33. The method of claim 32, wherein R^(a) is a methyl group, and the compound of Structure II has the Structure IIA having the following formula:


34. The method of claim 33, wherein the pharmaceutically acceptable salt of the compound of Structure IIA, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof is administered to the subject, and the salt is a lactate salt.
 35. The method of claim 32, wherein R^(a) is a hydrogen, and the compound of Structure II has the Structure IIB having the following formula:


36. The method of claim 32, wherein R^(a) is a methyl group, and the compound of Structure II has the Structure IIC having the following formula:


37. The method of claim 31, wherein the patient is a cancer patient.
 38. The method of claim 31, wherein R¹² and R¹³ are both H.
 39. The method of claim 31, further comprising withdrawing a sample of blood from the subject and then measuring the amount of the at least one cell adhesion molecule in at least a portion of the sample. 